Is STAT5B p.Leu162Phe (c.486A>T) pathogenic?

STAT5B p.Leu162Phe (c.486A>T) is classified Uncertain significance in STAT5B (ClinVar, Single submitter, 1 submitter; last evaluated 2019-08-30). AlphaMissense: likely pathogenic (0.7958); Very rare (popmax 0.0022%, sas).

How common is STAT5B p.Leu162Phe (c.486A>T) in the general population?

STAT5B p.Leu162Phe (c.486A>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about STAT5B p.Leu162Phe (c.486A>T)?

AlphaMissense predicts likely pathogenic (score 0.7958) — an in-silico prediction, not a clinical call.

STAT5B p.Leu162Phe

c.486A>T · VCV4935198

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7958 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.7958	likely pathogenic
REVEL	0.474	indeterminate
SaProt	LLR -10.27	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.074	GERP -0.075, phastCons 0.9
Regional constraint	o/e 0.54	unconstrained · MANE · 4,042 bp · p 2.1e-06 · regional, not allelic
Overall
CADD	21.7	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 0.0022% South Asian · 2/91,094 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.00062% 10/1,614,098 alleles · very rare exomes 6/1,461,892 · genomes 4/152,206 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,547
African / African-American	0.00133%	74,924
European (non-Finnish)	0.000593%	168,578

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.Leu162Phe
Coding: c.486A>T
MANE Select: NM_012448
Type: single nucleotide variant
Location: chr17:42223446 (GRCh38)
Gene constraint: LOEUF 0.277 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.90 · 2 PDB
Residue 162: an α-helix

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

Similar variants

STAT5B p.Leu162= Likely benign ★ same residue
STAT5B c.1906+1G>A Likely pathogenic ★★ same type
STAT5B p.Ala20Glu Uncertain significance ★★ ⚠ same type
STAT5B p.Ala20Val Uncertain significance ★★ ⚠ same type
STAT5B p.Ala213Gly Uncertain significance ★★ ⚠ same type
STAT5B p.Ala213Ser Uncertain significance ★★ ⚠ same type
STAT5B p.Ala723Thr Uncertain significance ★★ ⚠ same type
STAT5B p.Ala785Thr Uncertain significance ★★ ⚠ same type

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-leu162phe (accessed [today's date]).

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