PTPN22 rs2476601 and rs33996649: What These Variants Mean

Oct 4

4 min read

PTPN22 encodes a phosphatase in immune cells that helps regulate signaling. Two PTPN22 variants—rs2476601 (R620W) and rs33996649 (R263Q)—have been studied in relation to autoimmune disease, but they have different effects in research. The R620W variant is associated with higher odds of several conditions in population studies, while R263Q has shown lower odds for some conditions. Neither result predicts whether an individual will develop an autoimmune disease [R, R].

GenesUnveiled GeneExplorer includes both markers. You can explore the PTPN22 GeneExplorer page to see whether they are present in your raw DNA file.

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What Does the PTPN22 Gene Do?

PTPN22 provides instructions for making a protein tyrosine phosphatase called lymphoid tyrosine phosphatase, or LYP. The enzyme helps regulate signaling inside immune cells, including T cells. A primary functional study found that PTPN22 can limit T-cell receptor signaling, and that the R620W form more strongly inhibited early T-cell activation in the experimental systems studied [R].

This role is one reason PTPN22 is studied in autoimmunity: changes in immune-cell signaling can affect how the immune system responds to threats and maintains tolerance to the body’s own tissues. The complete biology is more complex than a simple “more” or “less” active immune system, and the effect of a variant can depend on the disease and population being studied.

PTPN22 Alleles and Strand Orientation

Research often describes these variants using the coding-strand letters in the gene sequence. A consumer raw DNA file may show complementary letters because PTPN22 is on the reverse genomic strand. GenesUnveiled reports forward-strand genotypes, so the allele labels can look different from the letters in some papers.

Marker	Protein change and common research notation	GenesUnveiled forward-strand mapping
rs2476601	R620W; coding-strand 1858C>T	A corresponds to the R620W form; G to R620
rs33996649	R263Q; coding-strand 788G>A	T corresponds to the R263Q form; C to R263

For this reason, check both the rsID and the strand convention when comparing a DNA report with a research paper. The “risk” or “protective” direction described below is specific to the marker and research context; it is not a prediction of personal health.

PTPN22 rs2476601: The R620W Variant

PTPN22 rs2476601 changes arginine to tryptophan at position 620 of the LYP protein. Research papers commonly call it R620W or C1858T. In the forward-strand genotype letters used by GenesUnveiled, A corresponds to the R620W form.

The R620W (A) allele has been associated with increased susceptibility to several autoimmune conditions, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Graves’ disease, and type 1 diabetes (T1D). A 2006 meta-analysis covering 29 studies and 43 disease comparisons reported odds ratios for the coding-strand 1858T allele of 1.58 for RA, 1.49 for SLE, 1.85 for Graves’ disease, and 1.61 for T1D [R].

The associations also vary by ancestry; the frequency of rs2476601 differs substantially among populations, and many of the early studies focused on European-ancestry groups [R].

The R620W allele has a clear functional effect on immune signaling, but scientists continue to investigate how that effect contributes to different autoimmune diseases.

Reading rs2476601 Genotypes

GG: No A (R620W) allele detected at this marker.
AG: One A (R620W) allele.
AA: Two A (R620W) alleles.

These genotypes describe the marker in the raw DNA file. They do not confirm or rule out autoimmune disease.

PTPN22 rs33996649: The R263Q Variant

PTPN22 rs33996649 changes arginine to glutamine at position 263, in the catalytic region of LYP. T corresponds to the Q263 form. Functional studies have found reduced phosphatase activity for R263Q. Genetic studies have reported lower odds for selected autoimmune outcomes, although evidence is more limited and not uniform across diseases.

In a six-country case-control study involving 5,579 people with RA and 5,392 controls, the T allele for R263Q was associated with lower odds of RA [R].

A separate meta-analysis found that the T allele was associated with lower odds of SLE, RA, and ulcerative colitis [R].

Reading rs33996649 Genotypes

CC: No T (R263Q) allele detected at this marker.
CT: One T (R263Q) allele.
TT: Two T (R263Q) alleles.

The T allele has shown protective associations for selected outcomes in research. It does not guarantee protection from RA, lupus, ulcerative colitis, or any other condition.

What Do PTPN22 Results Mean for Autoimmune Risk?

PTPN22 is one of many genes that researchers have linked to immune regulation. Its variants may shift susceptibility to particular conditions, but they do not work like diagnostic switches.

A result for rs2476601 or rs33996649 does not tell you:

whether you currently have an autoimmune disease;
whether symptoms are caused by autoimmunity;
your current immune-cell activity;
your absolute lifetime probability of developing a condition;
whether you need screening, medication, or treatment.

For context, compare PTPN22 with other immune-related GeneExplorer pages, including CTLA4 and IL23R. For a gene studied in Crohn’s disease, see NOD2.

Can Raw DNA Data Diagnose an Autoimmune Disease?

No. A raw DNA result identifies a genotype at a tested marker; it does not diagnose disease. Clinical evaluation may involve symptoms, examination, family history, and condition-specific laboratory tests.

GenesUnveiled GeneExplorer provides an educational interpretation of supported variants. It does not measure immune function or replace medical care. If you have symptoms or are concerned about autoimmune disease, discuss them with a qualified healthcare professional.

Why Might a PTPN22 Result Not Appear?

DNA testing companies do not all test the same markers, and coverage may differ between versions of the same company’s chip. A result appears only when the required marker is present and readable in the active raw DNA file.

If rs2476601 or rs33996649 is missing or recorded as a no-call, GenesUnveiled does not fill in the result by imputation or statistical guessing. The report is shown only when the genotype is available for direct analysis.

Explore PTPN22 in GeneExplorer

PTPN22 rs2476601 and rs33996649 are useful examples of how variants in the same gene can be associated with different directions of effect. R620W is linked to increased susceptibility for selected autoimmune diseases, while R263Q has shown lower odds for some conditions. Both findings depend on the disease, population, and quality of evidence.

GeneExplorer is free to use with a compatible raw DNA file. It can show whether these markers are present and help you explore the research behind them.