Is STAT5B p.Pro338Ser (c.1012C>T) pathogenic?

STAT5B p.Pro338Ser (c.1012C>T) is classified Uncertain significance in STAT5B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-23). AlphaMissense: likely pathogenic (0.9987); Absent from gnomAD v4.1; Associated with growth hormone insensitivity syndrome with immune dysregulation 2, autosomal dominant.

How common is STAT5B p.Pro338Ser (c.1012C>T) in the general population?

STAT5B p.Pro338Ser (c.1012C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about STAT5B p.Pro338Ser (c.1012C>T)?

AlphaMissense predicts likely pathogenic (score 0.9987) — an in-silico prediction, not a clinical call.

STAT5B p.Pro338Ser

Q: What condition is associated with STAT5B p.Pro338Ser (c.1012C>T)?

STAT5B p.Pro338Ser (c.1012C>T) is associated with growth hormone insensitivity syndrome with immune dysregulation 2, autosomal dominant (ClinVar).

c.1012C>T · rs2508756047 · VCV2444309

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9987 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

growth hormone insensitivity syndrome with immune dysregulation 2, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.9987	likely pathogenic · top 8% in STAT5B
REVEL	0.916	moderately pathogenic-leaning
SaProt	LLR -13.99	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.45	unconstrained · MANE · 629 bp · p 1.5e-08 · regional, not allelic
Overall
CADD	27.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: STAT5B
Protein: p.Pro338Ser
Coding: c.1012C>T
MANE Select: NM_012448
dbSNP: rs2508756047
Type: single nucleotide variant
Location: chr17:42218308 (GRCh38)
Gene constraint: LOEUF 0.277 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.90 · 2 PDB
Residue 338: an α-helix

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

Disease context

growth hormone insensitivity syndrome with immune dysregulation 2, autosomal dominant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

STAT5B p.Ala213Gly Uncertain significance ★★ ⚠ same condition
STAT5B p.Ala785Thr Uncertain significance ★★ ⚠ same condition
STAT5B p.Arg258Gln Uncertain significance ★★ ⚠ same condition
STAT5B p.Cys735Arg Uncertain significance ★★ same condition
STAT5B p.Glu269Lys Uncertain significance ★★ ⚠ same condition
STAT5B p.Gly721Ser Uncertain significance ★★ ⚠ same condition
STAT5B p.Ser556Thr Uncertain significance ★★ ⚠ same condition
STAT5B p.Ser787Pro 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-pro338ser (accessed [today's date]).

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