Is GATA4 p.Ala196Pro (c.586G>C) pathogenic?

GATA4 p.Ala196Pro (c.586G>C) is classified Uncertain significance in GATA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-11). AlphaMissense: likely benign (0.0942); Very rare (popmax 0.000262%, nfe); Associated with atrioventricular septal defect 4.

What condition is associated with GATA4 p.Ala196Pro (c.586G>C)?

GATA4 p.Ala196Pro (c.586G>C) is associated with atrioventricular septal defect 4 (ClinVar).

How common is GATA4 p.Ala196Pro (c.586G>C) in the general population?

GATA4 p.Ala196Pro (c.586G>C) is very rare (popmax 0.000262%, nfe) (gnomAD).

What do computational predictors say about GATA4 p.Ala196Pro (c.586G>C)?

AlphaMissense predicts likely benign (score 0.0942) — an in-silico prediction, not a clinical call.

GATA4 p.Ala196Pro

c.586G>C · rs1371654056 · VCV2053660

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0942 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000262%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

atrioventricular septal defect 4

Computational evidence

Protein change
AlphaMissense	0.0942	likely benign
REVEL	0.558	indeterminate
SaProt	LLR -5.80	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 2, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 41 kb · p 0.015 · regional, not allelic
Overall
CADD	19.72	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000262% European (non-Finnish) · 3/1,143,820 alleles

Filtering AF 7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000196% 3/1,527,920 alleles · very rare exomes 2/1,375,934 · genomes 1/151,986 · 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: GATA4
Protein: p.Ala196Pro
Coding: c.586G>C
MANE Select: NM_001308093
dbSNP: rs1371654056
Type: single nucleotide variant
Location: chr8:11708898 (GRCh38)
Gene constraint: LOEUF 0.468 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 58.64 · 3 PDB

Full GATA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

atrioventricular septal defect 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GATA4 p.Ala196Thr Uncertain significance ★★ ⚠ same residue
GATA4 p.Ala196= Likely benign ★★ same residue
GATA4 p.Ala196Ser Uncertain significance ★ ⚠ same residue
GATA4 p.Arg231Ter Pathogenic ★★ same condition
GATA4 p.Arg284His Pathogenic/Likely pathogenic ★★ same condition
GATA4 p.Gly297Ser Pathogenic/Likely pathogenic ★★ same condition
GATA4 c.1001-3C>T Uncertain significance ★★ same condition
GATA4 c.912+5G>A 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/gata4-p-ala196pro (accessed [today's date]).

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