Is JAK3 p.Pro38= (c.114C>A) pathogenic?

JAK3 p.Pro38= (c.114C>A) is classified Conflicting classifications of pathogenicity in JAK3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-03-31). Very rare (popmax 0.00338%, amr); Associated with T-B+ severe combined immunodeficiency due to JAK3 deficiency.

What condition is associated with JAK3 p.Pro38= (c.114C>A)?

JAK3 p.Pro38= (c.114C>A) is associated with T-B+ severe combined immunodeficiency due to JAK3 deficiency (ClinVar).

How common is JAK3 p.Pro38= (c.114C>A) in the general population?

JAK3 p.Pro38= (c.114C>A) is very rare (popmax 0.00338%, amr) (gnomAD).

JAK3 p.Pro38=

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.114C>A · rs1448668382 · VCV626122

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00338%, amr)

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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2.7	GERP -3.6
Overall
CADD	0.464	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00338% Admixed American · 2/59,242 alleles

Filtering AF 0.00056% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00021%

Overall 0.000435% 7/1,607,858 alleles · very rare exomes 4/1,455,740 · genomes 3/152,118 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00338%	29,621
African / African-American	0.00134%	74,798
European (non-Finnish)	0.00034%	294,527

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.Pro38=
Coding: c.114C>A
MANE Select: NM_000215
dbSNP: rs1448668382
Type: single nucleotide variant
Location: chr19:17844304 (GRCh38)
Gene constraint: LOEUF 0.933 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.20 · 43 PDB
Residue 38: the ferm domain; the 'interaction with cytokine/interferon/growth hormone receptors' region

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-pro38 (accessed [today's date]).

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