Is STAT5A p.Arg389Cys (c.1165C>T) pathogenic?

STAT5A p.Arg389Cys (c.1165C>T) is classified Uncertain significance in STAT5A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-10). AlphaMissense: likely benign (0.2211); Rare (popmax 0.247%, mid).

How common is STAT5A p.Arg389Cys (c.1165C>T) in the general population?

STAT5A p.Arg389Cys (c.1165C>T) is rare (popmax 0.247%, mid) (gnomAD).

What do computational predictors say about STAT5A p.Arg389Cys (c.1165C>T)?

AlphaMissense predicts likely benign (score 0.2211) — an in-silico prediction, not a clinical call.

STAT5A p.Arg389Cys

c.1165C>T · VCV3963117

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2211 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.247%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2211	likely benign
REVEL	0.53	indeterminate
SaProt	LLR -7.16	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.68 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 3,626 bp · p 2.4e-05 · regional, not allelic
Overall
CADD	25.7	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 0.247% Middle Eastern · 15/6,084 alleles

Filtering AF 0.152% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.123%

Overall 0.00192% 31/1,613,998 alleles · rare exomes 30/1,461,866 · genomes 1/152,132 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.247%	406
African / African-American	0.00534%	18,725
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
East Asian	0.00223%	44,880
South Asian	0.0022%	45,539
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	0.000593%	168,575

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.Arg389Cys
Coding: c.1165C>T
MANE Select: NM_001288718
Type: single nucleotide variant
Location: chr17:42301450 (GRCh38)
Gene constraint: LOEUF 0.364 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.78 · 5 PDB
Residue 389: a UniProt-annotated variant site (in)

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-arg389cys (accessed [today's date]).

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