Is ABCC8 p.Ala576Asp (c.1727C>A) pathogenic?

ABCC8 p.Ala576Asp (c.1727C>A) is classified Uncertain significance in ABCC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-01). AlphaMissense: likely pathogenic (0.9965); Absent from gnomAD v4.1.

How common is ABCC8 p.Ala576Asp (c.1727C>A) in the general population?

ABCC8 p.Ala576Asp (c.1727C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ABCC8 p.Ala576Asp (c.1727C>A)?

AlphaMissense predicts likely pathogenic (score 0.9965) — an in-silico prediction, not a clinical call.

ABCC8 p.Ala576Asp

c.1727C>A · VCV4774440

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9965 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9965	likely pathogenic · top 3% in ABCC8
REVEL	0.945	strongly pathogenic-leaning
SaProt	LLR -14.76	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 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 84 kb · p 1.4e-12 · regional, not allelic
Overall
CADD	33.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ABCC8
Protein: p.Ala576Asp
Coding: c.1727C>A
MANE Select: NM_000352
Type: single nucleotide variant
Location: chr11:17430904 (GRCh38)
Gene constraint: LOEUF 0.829 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 82.56 · 8 PDB
Residue 576: an α-helix; the abc transmembrane type-1 1 domain

Full ABCC8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABCC8 p.Ala576= Likely benign ★ same residue
ABCC8 c.1176+2T>C Pathogenic/Likely pathogenic ★★ same type
ABCC8 c.1333-1013A>G Pathogenic/Likely pathogenic ★★ same type
ABCC8 c.148+1G>A Pathogenic/Likely pathogenic ★★ same type
ABCC8 c.148+2T>G Likely pathogenic ★★ same type
ABCC8 c.1630+1G>A Pathogenic/Likely pathogenic ★★ same type
ABCC8 c.1630+1G>T Pathogenic ★★ same type
ABCC8 c.1817+1G>C Pathogenic ★★ 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/abcc8-p-ala576asp (accessed [today's date]).

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