Is STAT4 p.Phe340Leu (c.1020C>A) pathogenic?

STAT4 p.Phe340Leu (c.1020C>A) is classified Uncertain significance in STAT4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-06-20). AlphaMissense: likely pathogenic (0.9991); Very rare (popmax 0.00133%, afr); Associated with STAT4-related disorder.

What condition is associated with STAT4 p.Phe340Leu (c.1020C>A)?

STAT4 p.Phe340Leu (c.1020C>A) is associated with STAT4-related disorder (ClinVar).

How common is STAT4 p.Phe340Leu (c.1020C>A) in the general population?

STAT4 p.Phe340Leu (c.1020C>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about STAT4 p.Phe340Leu (c.1020C>A)?

AlphaMissense predicts likely pathogenic (score 0.9991) — an in-silico prediction, not a clinical call.

STAT4 p.Phe340Leu

c.1020C>A · rs941296401 · VCV1423404

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9991 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

STAT4-related disorder

Computational evidence

Protein change
AlphaMissense	0.9991	likely pathogenic · top 1% in STAT4
REVEL	0.919	moderately pathogenic-leaning
SaProt	LLR -11.68	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 9.9	GERP 1.1, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 114 kb · p 8.5e-09 · regional, not allelic
Overall
CADD	26.5	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 0.00133% African / African-American · 1/74,908 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,860 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,908
European (non-Finnish)	0.00017%	589,946

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.Phe340Leu
Coding: c.1020C>A
MANE Select: NM_003151
dbSNP: rs941296401
Type: single nucleotide variant
Location: chr2:191061743 (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

Disease context

STAT4-related disorder

Similar variants

STAT4 p.Gly618Glu Uncertain significance ★ ⚠ same condition
STAT4 p.Thr446Ile Conflicting classifications of pathogenicity ★ same condition
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

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-phe340leu (accessed [today's date]).

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