Is STAT5A p.Arg294His (c.881G>A) pathogenic?

STAT5A p.Arg294His (c.881G>A) is classified Uncertain significance in STAT5A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-16). AlphaMissense: ambiguous (0.4731); Ultra-rare (popmax 0.0138%, nfe).

How common is STAT5A p.Arg294His (c.881G>A) in the general population?

STAT5A p.Arg294His (c.881G>A) is ultra-rare (popmax 0.0138%, nfe) (gnomAD).

What do computational predictors say about STAT5A p.Arg294His (c.881G>A)?

AlphaMissense predicts ambiguous (score 0.4731) — an in-silico prediction, not a clinical call.

STAT5A p.Arg294His

c.881G>A · rs778262335 · VCV2383063

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4731 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0138%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4731	ambiguous
REVEL	0.342	indeterminate
SaProt	LLR -9.04	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 3,626 bp · p 2.4e-05 · regional, not allelic
Overall
CADD	32.0	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

Grpmax group 0.0138% European (non-Finnish) · 163/1,179,732 alleles

Filtering AF 0.0121% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0114%

Overall 0.0115% 186/1,613,096 alleles · ultra-rare exomes 175/1,461,052 · genomes 11/152,044 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.016%	6,241
European (non-Finnish)grpmax	0.0138%	7,238
Finnishnot grpmax-eligible	0.0125%	8,001
African / African-American	0.00401%	24,949
Admixed American	0.00167%	59,978
South Asian	0.0011%	91,046

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg294His
Coding: c.881G>A
MANE Select: NM_001288718
dbSNP: rs778262335
Type: single nucleotide variant
Location: chr17:42300762 (GRCh38)
Gene constraint: LOEUF 0.364 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.78 · 5 PDB
Residue 294: an α-helix

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-arg294his (accessed [today's date]).

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