Is STAT5B p.Phe416Cys (c.1247T>G) pathogenic?

STAT5B p.Phe416Cys (c.1247T>G) is classified Uncertain significance in STAT5B (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-03). AlphaMissense: likely pathogenic (0.9977); Very rare (popmax 0.000254%, nfe); Associated with Inborn genetic diseases.

What condition is associated with STAT5B p.Phe416Cys (c.1247T>G)?

STAT5B p.Phe416Cys (c.1247T>G) is associated with Inborn genetic diseases, growth hormone insensitivity with immune dysregulation 1, autosomal recessive (ClinVar).

How common is STAT5B p.Phe416Cys (c.1247T>G) in the general population?

STAT5B p.Phe416Cys (c.1247T>G) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about STAT5B p.Phe416Cys (c.1247T>G)?

AlphaMissense predicts likely pathogenic (score 0.9977) — an in-silico prediction, not a clinical call.

STAT5B p.Phe416Cys

c.1247T>G · rs2080181180 · VCV1678070

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9977 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9977	likely pathogenic
REVEL	0.983	strongly pathogenic-leaning
SaProt	LLR -11.77	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 0.96	unconstrained · MANE · 854 bp · p 0.7 · regional, not allelic
Overall
CADD	28.2	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

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,034 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,218 alleles · very rare exomes 3/1,461,894 · genomes 0/152,324 · 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.Phe416Cys
Coding: c.1247T>G
MANE Select: NM_012448
dbSNP: rs2080181180
Type: single nucleotide variant
Location: chr17:42217387 (GRCh38)
Gene constraint: LOEUF 0.277 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.90 · 2 PDB
Residue 416: a β-strand

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

Also linked: growth hormone insensitivity with immune dysregulation 1, autosomal recessive

Similar variants

STAT5B p.Phe416= Uncertain significance ★ same residue
STAT5B c.1906+1G>A Likely pathogenic ★★ same condition
STAT5B p.Ala20Glu Uncertain significance ★★ ⚠ same condition
STAT5B p.Ala20Val Uncertain significance ★★ ⚠ same condition
STAT5B p.Ala213Gly Uncertain significance ★★ ⚠ same condition
STAT5B p.Ala213Ser Uncertain significance ★★ ⚠ same condition
STAT5B p.Ala723Thr Uncertain significance ★★ ⚠ same condition
STAT5B p.Ala785Thr 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-phe416cys (accessed [today's date]).

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