Is ABCC8 p.Asp1193Val (c.3578A>T) pathogenic?

ABCC8 p.Asp1193Val (c.3578A>T) is classified Conflicting classifications of pathogenicity in ABCC8 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-10-09). AlphaMissense: likely pathogenic (0.7349); Ultra-rare (popmax 0.0706%, afr); Associated with hyperinsulinemic hypoglycemia, familial, 1.

What condition is associated with ABCC8 p.Asp1193Val (c.3578A>T)?

ABCC8 p.Asp1193Val (c.3578A>T) is associated with hyperinsulinemic hypoglycemia, familial, 1, type 2 diabetes mellitus, hypoglycemia, leucine-induced (ClinVar).

How common is ABCC8 p.Asp1193Val (c.3578A>T) in the general population?

ABCC8 p.Asp1193Val (c.3578A>T) is ultra-rare (popmax 0.0706%, afr) (gnomAD).

What do computational predictors say about ABCC8 p.Asp1193Val (c.3578A>T)?

AlphaMissense predicts likely pathogenic (score 0.7349) — an in-silico prediction, not a clinical call.

ABCC8 p.Asp1193Val

c.3578A>T · rs139486832 · VCV802658

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.7349 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0706%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyperinsulinemic hypoglycemia, familial, 1

Computational evidence

Protein change
AlphaMissense	0.7349	likely pathogenic
REVEL	0.937	strongly pathogenic-leaning
SaProt	LLR -4.27	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.8, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 84 kb · p 1.4e-12 · regional, not allelic
Overall
CADD	26.3	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 0.0706% African / African-American · 53/75,042 alleles

Filtering AF 0.0554% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.05%

Overall 0.00359% 58/1,614,180 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0706%	1,416
Admixed American	0.00333%	30,015
South Asian	0.00329%	30,359

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.Asp1193Val
Coding: c.3578A>T
MANE Select: NM_000352
dbSNP: rs139486832
Type: single nucleotide variant
Location: chr11:17402733 (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 1193: a turn; the abc transmembrane type-1 2 domain

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

Disease context

hyperinsulinemic hypoglycemia, familial, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: type 2 diabetes mellitus hypoglycemia, leucine-induced diabetes mellitus, transient neonatal, 2 diabetes mellitus, permanent neonatal 3

Similar variants

ABCC8 p.Asp1193= Likely benign ★ same residue
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

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-asp1193val (accessed [today's date]).

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