Is STAT5B p.Phe640Leu (c.1918T>C) pathogenic?

STAT5B p.Phe640Leu (c.1918T>C) is classified Uncertain significance in STAT5B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-10). AlphaMissense: likely pathogenic (0.8385); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with STAT5B p.Phe640Leu (c.1918T>C)?

STAT5B p.Phe640Leu (c.1918T>C) is associated with Inborn genetic diseases (ClinVar).

How common is STAT5B p.Phe640Leu (c.1918T>C) in the general population?

STAT5B p.Phe640Leu (c.1918T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about STAT5B p.Phe640Leu (c.1918T>C)?

AlphaMissense predicts likely pathogenic (score 0.8385) — an in-silico prediction, not a clinical call.

STAT5B p.Phe640Leu

c.1918T>C · VCV3802276

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8385 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8385	likely pathogenic
REVEL	0.239	benign-leaning
SaProt	LLR -5.48	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.3	GERP 1.1, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 7,379 bp · p 3.2e-06 · regional, not allelic
Overall
CADD	22.4	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

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.Phe640Leu
Coding: c.1918T>C
MANE Select: NM_012448
Type: single nucleotide variant
Location: chr17:42207717 (GRCh38)
Gene constraint: LOEUF 0.277 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.90 · 2 PDB
Residue 640: the sh2 domain

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-phe640leu (accessed [today's date]).

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