Is JAK2 p.Pro97Ala (c.289C>G) pathogenic?

JAK2 p.Pro97Ala (c.289C>G) is classified Uncertain significance in JAK2 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-05-25). AlphaMissense: likely benign (0.1461); Very rare (popmax 0.00034%, nfe); Associated with Inborn genetic diseases.

What condition is associated with JAK2 p.Pro97Ala (c.289C>G)?

JAK2 p.Pro97Ala (c.289C>G) is associated with Inborn genetic diseases (ClinVar).

How common is JAK2 p.Pro97Ala (c.289C>G) in the general population?

JAK2 p.Pro97Ala (c.289C>G) is very rare (popmax 0.00034%, nfe) (gnomAD).

What do computational predictors say about JAK2 p.Pro97Ala (c.289C>G)?

AlphaMissense predicts likely benign (score 0.1461) — an in-silico prediction, not a clinical call.

JAK2 p.Pro97Ala

c.289C>G · rs1823027113 · VCV2397750

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1461 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00034%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1461	likely benign
REVEL	0.318	indeterminate
SaProt	LLR -8.32	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 105 kb · p 0.1 · regional, not allelic
Overall
CADD	21.8	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

Grpmax group 0.00034% European (non-Finnish) · 4/1,177,076 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,610,418 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: JAK2
Protein: p.Pro97Ala
Coding: c.289C>G
MANE Select: NM_007179 · reported on NM_004972
dbSNP: rs1823027113
Type: single nucleotide variant
Location: chr9:5029845 (GRCh38)

Full JAK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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/jak2-p-pro97ala (accessed [today's date]).

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