Is STAT5A p.Ala733Pro (c.2197G>C) pathogenic?

STAT5A p.Ala733Pro (c.2197G>C) is classified Uncertain significance in STAT5A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-30). AlphaMissense: likely benign (0.0677); Ultra-rare (popmax 0.0332%, mid).

How common is STAT5A p.Ala733Pro (c.2197G>C) in the general population?

STAT5A p.Ala733Pro (c.2197G>C) is ultra-rare (popmax 0.0332%, mid) (gnomAD).

What do computational predictors say about STAT5A p.Ala733Pro (c.2197G>C)?

AlphaMissense predicts likely benign (score 0.0677) — an in-silico prediction, not a clinical call.

STAT5A p.Ala733Pro

c.2197G>C · VCV3802270

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0677 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0332%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0677	likely benign
REVEL	0.212	benign-leaning
SaProt	LLR -5.26	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.095	GERP -3.1, phastCons 0.046
Regional constraint	o/e 0.92	unconstrained · MANE · 1,232 bp · p 0.46 · regional, not allelic
Overall
CADD	3.68	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0332% Middle Eastern · 2/6,020 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0124%

Overall 0.00173% 28/1,613,852 alleles · ultra-rare exomes 26/1,461,670 · genomes 2/152,182 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0332%	3,010
Admixed American	0.025%	4,000
East Asian	0.00223%	44,890
European (non-Finnish)	0.000847%	117,995

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.Ala733Pro
Coding: c.2197G>C
MANE Select: NM_001288718
Type: single nucleotide variant
Location: chr17:42309459 (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-ala733pro (accessed [today's date]).

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