Is ABCC8 p.Ala640Val (c.1919C>T) pathogenic?

ABCC8 p.Ala640Val (c.1919C>T) is classified Uncertain significance in ABCC8 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-12-16). AlphaMissense: likely benign (0.0982); Ultra-rare (popmax 0.033%, mid); Associated with hyperinsulinemic hypoglycemia, familial, 1.

What condition is associated with ABCC8 p.Ala640Val (c.1919C>T)?

ABCC8 p.Ala640Val (c.1919C>T) is associated with hyperinsulinemic hypoglycemia, familial, 1 (ClinVar).

How common is ABCC8 p.Ala640Val (c.1919C>T) in the general population?

ABCC8 p.Ala640Val (c.1919C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about ABCC8 p.Ala640Val (c.1919C>T)?

AlphaMissense predicts likely benign (score 0.0982) — an in-silico prediction, not a clinical call.

ABCC8 p.Ala640Val

c.1919C>T · rs369049969 · VCV994764

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0982 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyperinsulinemic hypoglycemia, familial, 1

Computational evidence

Protein change
AlphaMissense	0.0982	likely benign
REVEL	0.713	pathogenic-leaning
SaProt	LLR -7.33	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.41 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.5	GERP 0.88, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 84 kb · p 1.4e-12 · regional, not allelic
Overall
CADD	24.8	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 0.033% Middle Eastern · 2/6,060 alleles

Filtering AF 0.0153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0146%

Overall 0.0134% 216/1,614,050 alleles · ultra-rare exomes 193/1,461,724 · genomes 23/152,326 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,030
European (non-Finnish)	0.0173%	5,784
Remaining individualsnot grpmax-eligible	0.0048%	20,836
Admixed American	0.00333%	30,013
Finnishnot grpmax-eligible	0.00313%	31,954
African / African-American	0.00266%	37,532
East Asian	0.00223%	44,872

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.Ala640Val
Coding: c.1919C>T
MANE Select: NM_000352
dbSNP: rs369049969
Type: single nucleotide variant
Location: chr11:17428569 (GRCh38)
Gene constraint: LOEUF 0.829 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 82.56 · 8 PDB

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

Similar variants

ABCC8 p.Ala640= Conflicting classifications of pathogenicity ★ same residue
ABCC8 p.Ala640Thr 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
ABCC8 c.1630+1G>T 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-ala640val (accessed [today's date]).

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