Is STAT3 p.Pro678His (c.2033C>A) pathogenic?

STAT3 p.Pro678His (c.2033C>A) is classified Uncertain significance in STAT3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-30). AlphaMissense: ambiguous (0.3935); Absent from gnomAD v4.1.

How common is STAT3 p.Pro678His (c.2033C>A) in the general population?

STAT3 p.Pro678His (c.2033C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about STAT3 p.Pro678His (c.2033C>A)?

AlphaMissense predicts ambiguous (score 0.3935) — an in-silico prediction, not a clinical call.

STAT3 p.Pro678His

c.2033C>A · rs2144679385 · VCV1678085

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3935 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3935	ambiguous
REVEL	0.872	moderately pathogenic-leaning
SaProt	LLR -11.68	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 10	GERP -0.44, phastCons 1
Regional constraint	o/e 0.49	unconstrained · MANE · 5,153 bp · p 0.00074 · regional, not allelic
Overall
CADD	33.0	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.Pro678His
Coding: c.2033C>A
MANE Select: NM_139276
dbSNP: rs2144679385
Type: single nucleotide variant
Location: chr17:42322350 (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

Similar variants

STAT3 p.Pro678= Likely benign ★ same residue
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

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-pro678his (accessed [today's date]).

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