Is STAT3 p.Met28Val (c.82A>G) pathogenic?

STAT3 p.Met28Val (c.82A>G) is classified Conflicting classifications of pathogenicity in STAT3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-11-14). AlphaMissense: likely pathogenic (0.637); Very rare (popmax 8.47e-05%, nfe); Associated with STAT3-related disorder.

What condition is associated with STAT3 p.Met28Val (c.82A>G)?

STAT3 p.Met28Val (c.82A>G) is associated with STAT3-related disorder (ClinVar).

How common is STAT3 p.Met28Val (c.82A>G) in the general population?

STAT3 p.Met28Val (c.82A>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about STAT3 p.Met28Val (c.82A>G)?

AlphaMissense predicts likely pathogenic (score 0.637) — an in-silico prediction, not a clinical call.

STAT3 p.Met28Val

c.82A>G · rs2145013673 · VCV1307011

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.637 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

STAT3-related disorder

Computational evidence

Protein change
AlphaMissense	0.637	likely pathogenic
REVEL	0.435	indeterminate
SaProt	LLR -7.25	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 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.39	unconstrained · MANE · 25 kb · p 2.4e-61 · regional, not allelic
Overall
CADD	26.9	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 8.47e-05% European (non-Finnish) · 1/1,180,010 alleles

Overall 6.84e-05% 1/1,461,830 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: STAT3
Protein: p.Met28Val
Coding: c.82A>G
MANE Select: NM_139276
dbSNP: rs2145013673
Type: single nucleotide variant
Location: chr17:42348435 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.80 · 6 PDB

Full STAT3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

STAT3-related disorder

Similar variants

STAT3 p.Arg152Trp Pathogenic ★★ ⚠ same condition
STAT3 p.Gly421Arg Pathogenic/Likely pathogenic ★★ ⚠ same condition
STAT3 p.His332Tyr Pathogenic/Likely pathogenic ★★ ⚠ same condition
STAT3 p.Thr716Met Pathogenic ★★ ⚠ same condition
STAT3 p.Cys718Tyr Uncertain significance ★★ ⚠ same condition
STAT3 c.551-1G>A Likely pathogenic ★ same condition
STAT3 p.Asn466Asp Likely pathogenic ★ same condition
STAT3 p.Lys340Glu Likely 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/stat3-p-met28val (accessed [today's date]).

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