Is JAK2 p.Ala391Pro (c.1171G>C) pathogenic?

JAK2 p.Ala391Pro (c.1171G>C) is classified Uncertain significance in JAK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-15). AlphaMissense: likely benign (0.2991); Very rare (popmax 0.00127%, nfe); Associated with Inborn genetic diseases.

What condition is associated with JAK2 p.Ala391Pro (c.1171G>C)?

JAK2 p.Ala391Pro (c.1171G>C) is associated with Inborn genetic diseases (ClinVar).

How common is JAK2 p.Ala391Pro (c.1171G>C) in the general population?

JAK2 p.Ala391Pro (c.1171G>C) is very rare (popmax 0.00127%, nfe) (gnomAD).

What do computational predictors say about JAK2 p.Ala391Pro (c.1171G>C)?

AlphaMissense predicts likely benign (score 0.2991) — an in-silico prediction, not a clinical call.

JAK2 p.Ala391Pro

c.1171G>C · VCV3679656

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2991 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00127%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.2991	likely benign
REVEL	0.075	moderately benign-leaning
SaProt	LLR -7.85	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 0.23	GERP -3.4
Regional constraint	o/e 1.04	unconstrained · MANE · 105 kb · p 0.1 · regional, not allelic
Overall
CADD	14.77	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 0.00127% European (non-Finnish) · 15/1,177,294 alleles

Filtering AF 0.000765% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000607%

Overall 0.00112% 18/1,608,332 alleles · very rare exomes 15/1,456,170 · genomes 3/152,162 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0047%	21,276
European (non-Finnish)grpmax	0.00127%	78,486

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala391Pro
Coding: c.1171G>C
MANE Select: NM_004972
Type: single nucleotide variant
Location: chr9:5064997 (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-ala391pro (accessed [today's date]).

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