Is ABCC8 p.Gly228Asp (c.683G>A) pathogenic?

ABCC8 p.Gly228Asp (c.683G>A) is classified Pathogenic/Likely pathogenic in ABCC8 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-01-05). AlphaMissense: likely pathogenic (0.9575); Very rare (popmax 0.00333%, amr); Associated with Autosomal dominant ABCC8-related disorders.

What condition is associated with ABCC8 p.Gly228Asp (c.683G>A)?

ABCC8 p.Gly228Asp (c.683G>A) is associated with Autosomal dominant ABCC8-related disorders, type 2 diabetes mellitus, hypoglycemia, leucine-induced (ClinVar).

How common is ABCC8 p.Gly228Asp (c.683G>A) in the general population?

ABCC8 p.Gly228Asp (c.683G>A) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about ABCC8 p.Gly228Asp (c.683G>A)?

AlphaMissense predicts likely pathogenic (score 0.9575) — an in-silico prediction, not a clinical call.

ABCC8 p.Gly228Asp

c.683G>A · rs863225280 · VCV217846

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

likely pathogenic

0.9575 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Autosomal dominant ABCC8-related disorders

Computational evidence

Protein change
AlphaMissense	0.9575	likely pathogenic ✓ concordant with ClinVar
REVEL	0.614	indeterminate
SaProt	LLR -10.05	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.4, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 84 kb · p 1.4e-12 · regional, not allelic
Overall
CADD	24.6	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 0.00333% Admixed American · 2/60,032 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000205% 3/1,461,894 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,016
European (non-Finnish)	8.47e-05%	1,180,043

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: ABCC8
Protein: p.Gly228Asp
Coding: c.683G>A
MANE Select: NM_000352
dbSNP: rs863225280
Type: single nucleotide variant
Location: chr11:17461722 (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 228: an α-helix

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

Disease context

Autosomal dominant ABCC8-related disorders

Also linked: type 2 diabetes mellitus hypoglycemia, leucine-induced hyperinsulinemic hypoglycemia, familial, 1 diabetes mellitus, transient neonatal, 2 familial hyperinsulinism maturity-onset diabetes of the young diabetes mellitus, permanent neonatal 3

Similar variants

ABCC8 c.1176+2T>C Pathogenic/Likely pathogenic ★★ same condition
ABCC8 c.1333-1013A>G Pathogenic/Likely pathogenic ★★ same condition
ABCC8 c.148+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCC8 c.148+2T>G Likely pathogenic ★★ same condition
ABCC8 c.1630+1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCC8 c.1630+1G>T Pathogenic ★★ same condition
ABCC8 c.1817+1G>C Pathogenic ★★ same condition
ABCC8 c.1817+2T>C Pathogenic/Likely pathogenic ★★ 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/abcc8-p-gly228asp (accessed [today's date]).

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