Is STAT5B p.Arg294Cys (c.880C>T) pathogenic?

STAT5B p.Arg294Cys (c.880C>T) is classified Uncertain significance in STAT5B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-25). AlphaMissense: ambiguous (0.5615); Very rare (popmax 0.0022%, sas); Associated with Inborn genetic diseases.

What condition is associated with STAT5B p.Arg294Cys (c.880C>T)?

STAT5B p.Arg294Cys (c.880C>T) is associated with Inborn genetic diseases (ClinVar).

How common is STAT5B p.Arg294Cys (c.880C>T) in the general population?

STAT5B p.Arg294Cys (c.880C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about STAT5B p.Arg294Cys (c.880C>T)?

AlphaMissense predicts ambiguous (score 0.5615) — an in-silico prediction, not a clinical call.

STAT5B p.Arg294Cys

c.880C>T · VCV4176413

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5615 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5615	ambiguous
REVEL	0.405	indeterminate
SaProt	LLR -11.04	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.45	unconstrained · MANE · 629 bp · p 1.5e-08 · regional, not allelic
Overall
CADD	33.0	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 0.0022% South Asian · 2/91,050 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000434% 7/1,613,358 alleles · very rare exomes 6/1,461,290 · genomes 1/152,068 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,525
African / African-American	0.00134%	74,884
European (non-Finnish)	0.000339%	294,949

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: STAT5B
Protein: p.Arg294Cys
Coding: c.880C>T
MANE Select: NM_012448
Type: single nucleotide variant
Location: chr17:42218832 (GRCh38)
Gene constraint: LOEUF 0.277 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.90 · 2 PDB
Residue 294: the 'required for interaction with nmi' region; an α-helix

Full STAT5B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

STAT5B p.Ala213Ser Uncertain significance ★★ ⚠ same condition
STAT5B p.Ala723Thr Uncertain significance ★★ ⚠ same condition
STAT5B p.Arg200Gln Uncertain significance ★★ ⚠ same condition
STAT5B p.Arg353Cys Uncertain significance ★★ ⚠ same condition
STAT5B p.Arg768Cys Uncertain significance ★★ ⚠ same condition
STAT5B p.Asn741Tyr Uncertain significance ★★ ⚠ same condition
STAT5B p.Asp157Tyr Uncertain significance ★★ ⚠ same condition
STAT5B p.Gln337Lys Uncertain significance ★★ ⚠ same condition

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/stat5b-p-arg294cys (accessed [today's date]).

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