Is JAK1 p.Ser22Pro (c.64T>C) pathogenic?

JAK1 p.Ser22Pro (c.64T>C) is classified Uncertain significance in JAK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-12-31). AlphaMissense: likely benign (0.1567); Absent from gnomAD v4.1.

How common is JAK1 p.Ser22Pro (c.64T>C) in the general population?

JAK1 p.Ser22Pro (c.64T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about JAK1 p.Ser22Pro (c.64T>C)?

AlphaMissense predicts likely benign (score 0.1567) — an in-silico prediction, not a clinical call.

JAK1 p.Ser22Pro

c.64T>C · rs2101267269 · VCV1389135

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1567 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1567	likely benign
REVEL	0.364	indeterminate
SaProt	LLR -7.18	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP 5.3, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 26 kb · p 2.2e-10 · regional, not allelic
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: JAK1
Protein: p.Ser22Pro
Coding: c.64T>C
MANE Select: NM_002227
dbSNP: rs2101267269
Type: single nucleotide variant
Location: chr1:64883418 (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.Ser22Phe Uncertain significance ★ ⚠ same residue
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

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-ser22pro (accessed [today's date]).

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