Is ABCC8 p.Ala269Asp (c.806C>A) pathogenic?

ABCC8 p.Ala269Asp (c.806C>A) is classified Uncertain significance in ABCC8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-08). AlphaMissense: ambiguous (0.4595); Very rare (popmax 0.0022%, nfe); Associated with hyperinsulinemic hypoglycemia, familial, 1.

What condition is associated with ABCC8 p.Ala269Asp (c.806C>A)?

ABCC8 p.Ala269Asp (c.806C>A) is associated with hyperinsulinemic hypoglycemia, familial, 1, type 2 diabetes mellitus, hypoglycemia, leucine-induced (ClinVar).

How common is ABCC8 p.Ala269Asp (c.806C>A) in the general population?

ABCC8 p.Ala269Asp (c.806C>A) is very rare (popmax 0.0022%, nfe) (gnomAD).

What do computational predictors say about ABCC8 p.Ala269Asp (c.806C>A)?

AlphaMissense predicts ambiguous (score 0.4595) — an in-silico prediction, not a clinical call.

ABCC8 p.Ala269Asp

c.806C>A · rs372930264 · VCV1321361

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4595 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hyperinsulinemic hypoglycemia, familial, 1

Computational evidence

Protein change
AlphaMissense	0.4595	ambiguous
REVEL	0.802	moderately pathogenic-leaning
SaProt	LLR -12.78	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.83 · evaluated, not missing
Constraint at this position
Conservation	phyloP 8.6	GERP 1.3, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 84 kb · p 1.4e-12 · regional, not allelic
Overall
CADD	26.5	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 0.0022% European (non-Finnish) · 26/1,180,048 alleles

Filtering AF 0.00153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00161% 26/1,614,100 alleles · very rare

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.Ala269Asp
Coding: c.806C>A
MANE Select: NM_000352
dbSNP: rs372930264
Type: single nucleotide variant
Location: chr11:17461599 (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 269: an α-helix

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.Ala269fs Pathogenic/Likely pathogenic ★★ same residue
ABCC8 p.Ala269Val Uncertain significance ★★ ⚠ same residue
ABCC8 p.Ala269Thr Uncertain significance ⚠ 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

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-ala269asp (accessed [today's date]).

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