Is JAK3 p.Pro151Arg (c.452C>G) pathogenic?

JAK3 p.Pro151Arg (c.452C>G) is classified Benign in JAK3 (ClinVar, Expert panel, 10 submitters; last evaluated 2024-01-23). AlphaMissense: likely benign (0.0754); Low-frequency (popmax 1.45%, mid); Associated with T-B+ severe combined immunodeficiency due to JAK3 deficiency.

What condition is associated with JAK3 p.Pro151Arg (c.452C>G)?

JAK3 p.Pro151Arg (c.452C>G) is associated with T-B+ severe combined immunodeficiency due to JAK3 deficiency (ClinVar).

How common is JAK3 p.Pro151Arg (c.452C>G) in the general population?

JAK3 p.Pro151Arg (c.452C>G) is low-frequency (popmax 1.45%, mid) (gnomAD).

What do computational predictors say about JAK3 p.Pro151Arg (c.452C>G)?

AlphaMissense predicts likely benign (score 0.0754) — an in-silico prediction, not a clinical call.

JAK3 p.Pro151Arg

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.452C>G · rs55778349 · VCV36422

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.0754 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.45%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

T-B+ severe combined immunodeficiency due to JAK3 deficiency

ClinGen expert panel — Severe Combined Immunodeficiency Disease VCEP

Benign for T-B+ severe combined immunodeficiency due to JAK3 deficiency. Applied ACMG criteria (verbatim):

BS2_Supporting BA1

Curation rationale (ClinGen, verbatim)

The NM_000215.4(JAK3):c.452C>G (p.Pro151Arg) variant in JAK3 is a missense variant predicted to cause the substitution of Proline by Arginine at amino acid 151 (p.Pro151Arg). The Popmax Filtering allele frequency (95% CI) of the variant is 0.008679 in gnomAD v.4 for European (non-Finnish) population 10486/1179548 alleles, which is higher than the ClinGen SCID VCEP threshold (>0.00447) for BA1, therefore, meets this criterion (BA1). Also, 59 homozygous adults are reported on GnomAD v2.1.1 (BS2_Supporting). In summary, this variant meets the criteria to be classified as Benign for autosomal recessive T-B+ severe combined immunodeficiency due to JAK3 deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen SCID VCEP. Criteria applied: BA1 and BS2_Supporting (VCEP specifications version 1.0).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.0754	likely benign
REVEL	0.446	indeterminate
SaProt	LLR -6.06	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.2	GERP -2.6, phastCons 0.036
Regional constraint	o/e 0.97	unconstrained · MANE · 5,086 bp · p 0.45 · regional, not allelic
Overall
CADD	6.287	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.45% Middle Eastern · 88/6,052 alleles

Filtering AF 1.21% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.12%

Overall 0.777% 12,489/1,608,004 alleles · low-frequency exomes 11,511/1,455,712 · genomes 978/152,292 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	1.45%	69
Finnishnot grpmax-eligible	0.986%	101
European (non-Finnish)	0.889%	112
Ashkenazi Jewishnot grpmax-eligible	0.856%	117
Remaining individualsnot grpmax-eligible	0.77%	130
Amishnot grpmax-eligible	0.439%	228
South Asian	0.371%	270
Admixed American	0.239%	419
African / African-American	0.155%	646
East Asian	0.00223%	44,846

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.Pro151Arg
Coding: c.452C>G
MANE Select: NM_000215
dbSNP: rs55778349
Type: single nucleotide variant
Location: chr19:17843141 (GRCh38)
Gene constraint: LOEUF 0.933 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.20 · 43 PDB
Residue 151: the ferm domain; a UniProt-annotated variant site (in t(-)b(+)nk(-) scid; likely benign); 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 p.Pro151= Likely benign ★ same residue
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

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-pro151arg (accessed [today's date]).

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