Is STAT3 p.Met331Arg (c.992T>G) pathogenic?

STAT3 p.Met331Arg (c.992T>G) is classified Likely pathogenic in STAT3 (ClinVar, Single submitter, 1 submitter; last evaluated 2015-07-18). AlphaMissense: likely pathogenic (0.9015); Absent from gnomAD v4.1.

How common is STAT3 p.Met331Arg (c.992T>G) in the general population?

STAT3 p.Met331Arg (c.992T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about STAT3 p.Met331Arg (c.992T>G)?

AlphaMissense predicts likely pathogenic (score 0.9015) — an in-silico prediction, not a clinical call.

STAT3 p.Met331Arg

c.992T>G · rs1085307931 · VCV427058

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9015 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9015	likely pathogenic ✓ concordant with ClinVar
REVEL	0.636	indeterminate
SaProt	LLR -5.14	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.1	GERP -1.3, phastCons 1
Regional constraint	o/e 0.39	unconstrained · MANE · 25 kb · p 2.4e-61 · regional, not allelic
Overall
CADD	27.9	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

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: STAT3
Protein: p.Met331Arg
Coding: c.992T>G
MANE Select: NM_139276
dbSNP: rs1085307931
Type: single nucleotide variant
Location: chr17:42333730 (GRCh38)
Gene constraint: LOEUF 0.109 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.80 · 6 PDB
Residue 331: a UniProt-annotated variant site (in admio1; uncertain significance)

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

Similar variants

STAT3 p.Arg152Trp Pathogenic ★★ ⚠ same type
STAT3 p.Arg278Cys Likely pathogenic ★★ same type
STAT3 p.Arg335Trp Pathogenic/Likely pathogenic ★★ same type
STAT3 p.Arg382Gln Pathogenic ★★ same type
STAT3 p.Arg382Trp Pathogenic ★★ same type
STAT3 p.Arg423Gln Pathogenic ★★ ⚠ same type
STAT3 p.Asn466Ser Pathogenic ★★ ⚠ same type
STAT3 p.Asn466Thr Pathogenic/Likely pathogenic ★★ ⚠ 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/stat3-p-met331arg (accessed [today's date]).

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