Is STAT5A p.Pro491Arg (c.1472C>G) pathogenic?

STAT5A p.Pro491Arg (c.1472C>G) is classified Uncertain significance in STAT5A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-31). AlphaMissense: likely pathogenic (0.7725); Very rare (popmax 0.008%, afr).

How common is STAT5A p.Pro491Arg (c.1472C>G) in the general population?

STAT5A p.Pro491Arg (c.1472C>G) is very rare (popmax 0.008%, afr) (gnomAD).

What do computational predictors say about STAT5A p.Pro491Arg (c.1472C>G)?

AlphaMissense predicts likely pathogenic (score 0.7725) — an in-silico prediction, not a clinical call.

STAT5A p.Pro491Arg

c.1472C>G · VCV3323186

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7725 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.008%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7725	likely pathogenic
REVEL	0.671	pathogenic-leaning
SaProt	LLR -8.36	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.3	GERP 1.7, phastCons 1
Regional constraint	o/e 0.49	unconstrained · MANE · 5,082 bp · p 4.9e-26 · regional, not allelic
Overall
CADD	26.8	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 0.008% African / African-American · 6/75,014 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00228%

Overall 0.00062% 10/1,613,956 alleles · very rare exomes 4/1,461,706 · genomes 6/152,250 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.008%	12,502
Admixed American	0.00666%	15,004

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: STAT5A
Protein: p.Pro491Arg
Coding: c.1472C>G
MANE Select: NM_001288718
Type: single nucleotide variant
Location: chr17:42305701 (GRCh38)
Gene constraint: LOEUF 0.364 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.78 · 5 PDB

Full STAT5A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

STAT5A c.2063-4A>G Benign ★★ same type
STAT5A p.Asp743= Benign ★★ same type
STAT5A p.Leu746= Benign ★★ same type
STAT5A p.Val209Ala Benign ★★ same type
STAT5A p.Ala213Val Uncertain significance ★ ⚠ same type
STAT5A p.Ala318Thr Uncertain significance ★ ⚠ same type
STAT5A p.Ala45Ser Uncertain significance ★ ⚠ same type
STAT5A p.Ala510Thr Uncertain significance ★ ⚠ 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/stat5a-p-pro491arg (accessed [today's date]).

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