Is STAT4 p.Phe638Leu (c.1914C>A) pathogenic?

STAT4 p.Phe638Leu (c.1914C>A) is classified Uncertain significance in STAT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-21). AlphaMissense: likely pathogenic (0.8477); Very rare (popmax 0.00667%, afr).

How common is STAT4 p.Phe638Leu (c.1914C>A) in the general population?

STAT4 p.Phe638Leu (c.1914C>A) is very rare (popmax 0.00667%, afr) (gnomAD).

What do computational predictors say about STAT4 p.Phe638Leu (c.1914C>A)?

AlphaMissense predicts likely pathogenic (score 0.8477) — an in-silico prediction, not a clinical call.

STAT4 p.Phe638Leu

c.1914C>A · rs369720896 · VCV2071343

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8477 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8477	likely pathogenic
REVEL	0.584	indeterminate
SaProt	LLR -6.95	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.53	acceptor gain · deltas
Pangolin	Δ0.41	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -4	GERP -3.4
Regional constraint	o/e 0.48	unconstrained · MANE · 1,552 bp · p 1e-10 · regional, not allelic
Overall
CADD	17.2	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 0.00667% African / African-American · 5/74,934 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.000434% 7/1,614,086 alleles · very rare exomes 2/1,461,882 · genomes 5/152,204 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00667%	14,987
Remaining individualsnot grpmax-eligible	0.0032%	31,243

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.Phe638Leu
Coding: c.1914C>A
MANE Select: NM_003151
dbSNP: rs369720896
Type: single nucleotide variant
Location: chr2:191033088 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI 0.93 (gnomAD)
Structure: AlphaFold pLDDT 86.87
Residue 638: the sh2 domain

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

Similar variants

STAT4 p.Phe638= Likely benign ★ 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-phe638leu (accessed [today's date]).

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