Is STAT4 p.Ala46Val (c.137C>T) pathogenic?

STAT4 p.Ala46Val (c.137C>T) is classified Uncertain significance in STAT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-08). AlphaMissense: ambiguous (0.5397); Very rare (popmax 8.72e-05%, nfe).

How common is STAT4 p.Ala46Val (c.137C>T) in the general population?

STAT4 p.Ala46Val (c.137C>T) is very rare (popmax 8.72e-05%, nfe) (gnomAD).

What do computational predictors say about STAT4 p.Ala46Val (c.137C>T)?

AlphaMissense predicts ambiguous (score 0.5397) — an in-silico prediction, not a clinical call.

STAT4 p.Ala46Val

c.137C>T · VCV3648543

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5397 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.72e-05%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5397	ambiguous
REVEL	0.254	benign-leaning
SaProt	LLR -8.51	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 114 kb · p 8.5e-09 · regional, not allelic
Overall
CADD	25.4	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

Grpmax group 8.72e-05% European (non-Finnish) · 1/1,147,160 alleles

Overall 6.5e-05% 1/1,537,942 alleles · very rare exomes 1/1,386,450 · genomes 0/151,492 · 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: STAT4
Protein: p.Ala46Val
Coding: c.137C>T
MANE Select: NM_003151
Type: single nucleotide variant
Location: chr2:191146749 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI 0.93 (gnomAD)
Structure: AlphaFold pLDDT 86.87

Full STAT4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

STAT4 p.Ala46Ser Uncertain significance ★ ⚠ same residue
STAT4 p.Ala245Thr Uncertain significance ★★ ⚠ same type
STAT4 p.Arg241Gln Uncertain significance ★★ ⚠ same type
STAT4 p.Arg70Leu Uncertain significance ★★ ⚠ same type
STAT4 p.Arg87Lys Uncertain significance ★★ ⚠ same type
STAT4 p.Asp513Val Uncertain significance ★★ ⚠ same type
STAT4 p.Cys323Arg Uncertain significance ★★ ⚠ same type
STAT4 p.Gln243Lys 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/stat4-p-ala46val (accessed [today's date]).

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