Is JAK1 p.Phe15Ser (c.44T>C) pathogenic?

JAK1 p.Phe15Ser (c.44T>C) is classified Uncertain significance in JAK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-14). AlphaMissense: likely pathogenic (0.9658); Very rare (popmax 0.004%, afr).

How common is JAK1 p.Phe15Ser (c.44T>C) in the general population?

JAK1 p.Phe15Ser (c.44T>C) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about JAK1 p.Phe15Ser (c.44T>C)?

AlphaMissense predicts likely pathogenic (score 0.9658) — an in-silico prediction, not a clinical call.

JAK1 p.Phe15Ser

c.44T>C · rs766817040 · VCV2986669

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9658 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9658	likely pathogenic
REVEL	0.477	indeterminate
SaProt	LLR -6.18	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 6.6, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 26 kb · p 2.2e-10 · regional, not allelic
Overall
CADD	24.8	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 0.004% African / African-American · 3/74,918 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.00197% 3/152,180 alleles · very rare

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: JAK1
Protein: p.Phe15Ser
Coding: c.44T>C
MANE Select: NM_002227
dbSNP: rs766817040
Type: single nucleotide variant
Location: chr1:64883438 (GRCh38)
Gene constraint: LOEUF 0.168 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.68 · 52 PDB

Full JAK1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

JAK1 p.Arg1113Cys Uncertain significance ★★ ⚠ same type
JAK1 p.Arg1113His Uncertain significance ★★ ⚠ same type
JAK1 p.Arg219Gln Uncertain significance ★★ ⚠ same type
JAK1 p.Arg360Trp Uncertain significance ★★ ⚠ same type
JAK1 p.Arg454Trp Uncertain significance ★★ ⚠ same type
JAK1 p.Arg49Trp Uncertain significance ★★ ⚠ same type
JAK1 p.Arg514Cys Uncertain significance ★★ ⚠ same type
JAK1 p.Arg809Gln Uncertain significance ★★ ⚠ same type

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/jak1-p-phe15ser (accessed [today's date]).

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