Is GATA6 p.Pro399Ser (c.1195C>T) pathogenic?

GATA6 p.Pro399Ser (c.1195C>T) is classified Uncertain significance in GATA6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-20). AlphaMissense: likely pathogenic (0.9968); Absent from gnomAD v4.1; Associated with atrioventricular septal defect 5.

What condition is associated with GATA6 p.Pro399Ser (c.1195C>T)?

GATA6 p.Pro399Ser (c.1195C>T) is associated with atrioventricular septal defect 5 (ClinVar).

How common is GATA6 p.Pro399Ser (c.1195C>T) in the general population?

GATA6 p.Pro399Ser (c.1195C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GATA6 p.Pro399Ser (c.1195C>T)?

AlphaMissense predicts likely pathogenic (score 0.9968) — an in-silico prediction, not a clinical call.

GATA6 p.Pro399Ser

c.1195C>T · VCV3605810

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9968 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,578,470)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

atrioventricular septal defect 5

Computational evidence

Protein change
AlphaMissense	0.9968	likely pathogenic · top 7% in GATA6
REVEL	0.891	moderately pathogenic-leaning
SaProt	LLR -12.32	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 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 4,563 bp · p 0.00049 · regional, not allelic
Overall
CADD	27.4	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

No allele count reported in gnomAD v4.1 (AN 1,578,470). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: GATA6
Protein: p.Pro399Ser
Coding: c.1195C>T
MANE Select: NM_005257
Type: single nucleotide variant
Location: chr18:22177014 (GRCh38)
Gene constraint: LOEUF 0.527 · pLI 0.95 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.48

Full GATA6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

atrioventricular septal defect 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GATA6 p.Pro399Leu Uncertain significance ★★ ⚠ same residue
GATA6 c.1135+2T>C Likely pathogenic ★★ same condition
GATA6 p.Arg456Cys Pathogenic ★★ same condition
GATA6 p.Arg493Ter Pathogenic ★★ same condition
GATA6 p.Ala122Ser Uncertain significance ★★ ⚠ same condition
GATA6 p.Ala122Thr Uncertain significance ★★ ⚠ same condition
GATA6 p.Ala124Thr Uncertain significance ★★ ⚠ same condition
GATA6 p.Ala134Asp 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/gata6-p-pro399ser (accessed [today's date]).

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