Is STAT5B p.Arg121Gly (c.361C>G) pathogenic?

STAT5B p.Arg121Gly (c.361C>G) is classified Uncertain significance in STAT5B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-12). AlphaMissense: likely benign (0.1554); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with STAT5B p.Arg121Gly (c.361C>G)?

STAT5B p.Arg121Gly (c.361C>G) is associated with Inborn genetic diseases (ClinVar).

How common is STAT5B p.Arg121Gly (c.361C>G) in the general population?

STAT5B p.Arg121Gly (c.361C>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about STAT5B p.Arg121Gly (c.361C>G)?

AlphaMissense predicts likely benign (score 0.1554) — an in-silico prediction, not a clinical call.

STAT5B p.Arg121Gly

c.361C>G · rs2080259377 · VCV3171130

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1554 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1554	likely benign
REVEL	0.204	benign-leaning
SaProt	LLR -8.72	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.44 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 1,340 bp · p 0.55 · regional, not allelic
Overall
CADD	23.8	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 8.48e-05% European (non-Finnish) · 1/1,179,812 alleles

Overall 6.2e-05% 1/1,613,722 alleles · very rare exomes 1/1,461,600 · genomes 0/152,122 · joint denominator

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.Arg121Gly
Coding: c.361C>G
MANE Select: NM_012448
dbSNP: rs2080259377
Type: single nucleotide variant
Location: chr17:42224793 (GRCh38)
Gene constraint: LOEUF 0.277 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.90 · 2 PDB

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.Arg121Pro Uncertain significance ★ ⚠ same residue
STAT5B p.Arg121Leu Uncertain significance ★★ ⚠ same residue
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

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-arg121gly (accessed [today's date]).

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