Is JAK3 p.Pro665= (c.1995C>T) pathogenic?

JAK3 p.Pro665= (c.1995C>T) is classified Benign/Likely benign in JAK3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-14). Rare (popmax 0.354%, afr); Associated with T-B+ severe combined immunodeficiency due to JAK3 deficiency.

What condition is associated with JAK3 p.Pro665= (c.1995C>T)?

JAK3 p.Pro665= (c.1995C>T) is associated with T-B+ severe combined immunodeficiency due to JAK3 deficiency (ClinVar).

How common is JAK3 p.Pro665= (c.1995C>T) in the general population?

JAK3 p.Pro665= (c.1995C>T) is rare (popmax 0.354%, afr) (gnomAD).

JAK3 p.Pro665=

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.1995C>T · rs3212768 · VCV532751

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.354%, afr)

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 -1.6	GERP -3.7
Overall
CADD	2.217	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.354% African / African-American · 266/75,072 alleles

Filtering AF 0.319% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.306%

Overall 0.018% 291/1,614,208 alleles · rare exomes 140/1,461,884 · genomes 151/152,324 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.354%	282
Admixed American	0.0183%	5,456
Remaining individualsnot grpmax-eligible	0.0176%	5,683
South Asian	0.0011%	91,080
European (non-Finnish)	0.000169%	590,016

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.Pro665=
Coding: c.1995C>T
MANE Select: NM_000215
dbSNP: rs3212768
Type: single nucleotide variant
Location: chr19:17835135 (GRCh38)
Gene constraint: LOEUF 0.933 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.20 · 43 PDB
Residue 665: the protein kinase 1 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-pro665 (accessed [today's date]).

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