Is STAT1 p.Pro251Leu (c.752C>T) pathogenic?

STAT1 p.Pro251Leu (c.752C>T) is classified Likely pathogenic in STAT1 (ClinVar, Single submitter, 1 submitter; last evaluated 2016-11-02). AlphaMissense: ambiguous (0.4296); Very rare (popmax 0.00133%, afr).

How common is STAT1 p.Pro251Leu (c.752C>T) in the general population?

STAT1 p.Pro251Leu (c.752C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about STAT1 p.Pro251Leu (c.752C>T)?

AlphaMissense predicts ambiguous (score 0.4296) — an in-silico prediction, not a clinical call.

STAT1 p.Pro251Leu

c.752C>T · rs778254943 · VCV422527

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4296 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4296	ambiguous
REVEL	0.657	pathogenic-leaning
SaProt	LLR -11.20	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.42	unconstrained · MANE · 5,939 bp · p 3.1e-13 · regional, not allelic
Overall
CADD	29.8	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 0.00133% African / African-American · 1/75,032 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,614,186 alleles · very rare exomes 4/1,461,886 · genomes 0/152,300 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,032
European (non-Finnish)	0.000254%	393,349

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: STAT1
Protein: p.Pro251Leu
Coding: c.752C>T
MANE Select: NM_007315
dbSNP: rs778254943
Type: single nucleotide variant
Location: chr2:190997889 (GRCh38)
Gene constraint: LOEUF 0.271 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 87.78 · 10 PDB

Full STAT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

STAT1 p.Pro251= Likely benign ★★ same residue
STAT1 p.Pro251fs Likely pathogenic ★ same residue
STAT1 p.Ala267Val Pathogenic ★★ ⚠ same type
STAT1 p.Arg274Gln Pathogenic ★★ ⚠ same type
STAT1 p.Arg274Gly Pathogenic/Likely pathogenic ★★ same type
STAT1 p.Arg274Trp Pathogenic ★★ same type
STAT1 p.Asp171Asn Likely pathogenic ★★ ⚠ same type
STAT1 p.Asp292Glu 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/stat1-p-pro251leu (accessed [today's date]).

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