Is JAK3 p.Glu331= (c.993G>A) pathogenic?

JAK3 p.Glu331= (c.993G>A) is classified Likely benign in JAK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-14). Ultra-rare (popmax 0.0564%, sas); Associated with T-B+ severe combined immunodeficiency due to JAK3 deficiency.

What condition is associated with JAK3 p.Glu331= (c.993G>A)?

JAK3 p.Glu331= (c.993G>A) is associated with T-B+ severe combined immunodeficiency due to JAK3 deficiency (ClinVar).

How common is JAK3 p.Glu331= (c.993G>A) in the general population?

JAK3 p.Glu331= (c.993G>A) is ultra-rare (popmax 0.0564%, sas) (gnomAD).

JAK3 p.Glu331=

Q: How is T-B+ severe combined immunodeficiency due to JAK3 deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.993G>A · rs200738540 · VCV1967912

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0564%, sas)

Conditions

T-B+ severe combined immunodeficiency due to JAK3 deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP -0.53, phastCons 1
Overall
CADD	11.13	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0564% South Asian · 50/88,582 alleles

Filtering AF 0.0439% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0395%

Overall 0.00339% 54/1,590,586 alleles · ultra-rare exomes 52/1,438,360 · genomes 2/152,226 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0564%	1,772
Remaining individualsnot grpmax-eligible	0.00325%	30,791
African / African-American	0.00268%	37,283

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: JAK3
Protein: p.Glu331=
Coding: c.993G>A
MANE Select: NM_000215
dbSNP: rs200738540
Type: single nucleotide variant
Location: chr19:17841538 (GRCh38)
Gene constraint: LOEUF 0.933 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.20 · 43 PDB
Residue 331: the ferm domain

Full JAK3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

T-B+ severe combined immunodeficiency due to JAK3 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For T-B+ severe combined immunodeficiency due to JAK3 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

JAK3 c.1701+1G>A Likely pathogenic ★★★ same condition
JAK3 c.2680+89G>A Likely pathogenic ★★★ same condition
JAK3 c.862-2A>G Likely pathogenic ★★★ same condition
JAK3 p.Arg350Trp Likely pathogenic ★★★ same condition
JAK3 p.Arg403His Likely pathogenic ★★★ ⚠ same condition
JAK3 p.Arg445Ter Pathogenic ★★★ same condition
JAK3 p.Arg451Ter Pathogenic ★★★ same condition
JAK3 p.Arg582Trp Likely pathogenic ★★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/jak3-p-glu331 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown