Is ABCC8 p.Glu1442Val (c.4325A>T) pathogenic?

ABCC8 p.Glu1442Val (c.4325A>T) is classified Conflicting classifications of pathogenicity in ABCC8 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-06-04). AlphaMissense: likely pathogenic (0.5729); Ultra-rare (popmax 0.0478%, sas); Associated with maturity-onset diabetes of the young.

What condition is associated with ABCC8 p.Glu1442Val (c.4325A>T)?

ABCC8 p.Glu1442Val (c.4325A>T) is associated with maturity-onset diabetes of the young, hyperinsulinemic hypoglycemia, familial, 1, transient neonatal diabetes mellitus (ClinVar).

How common is ABCC8 p.Glu1442Val (c.4325A>T) in the general population?

ABCC8 p.Glu1442Val (c.4325A>T) is ultra-rare (popmax 0.0478%, sas) (gnomAD).

How is MODY inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ABCC8 p.Glu1442Val (c.4325A>T)?

AlphaMissense predicts likely pathogenic (score 0.5729) — an in-silico prediction, not a clinical call.

ABCC8 p.Glu1442Val

c.4325A>T · rs562680077 · VCV830318

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.5729 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0478%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

maturity-onset diabetes of the young

Computational evidence

Protein change
AlphaMissense	0.5729	likely pathogenic
REVEL	0.807	moderately pathogenic-leaning
SaProt	LLR -9.21	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 7.9	GERP 2.7, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 84 kb · p 1.4e-12 · regional, not allelic
Overall
CADD	26.8	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 0.0478% South Asian · 42/87,906 alleles

Filtering AF 0.0363% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0322%

Overall 0.0027% 43/1,594,844 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0478%	2,093
Remaining individualsnot grpmax-eligible	0.00162%	61,706

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.Glu1442Val
Coding: c.4325A>T
MANE Select: NM_000352
dbSNP: rs562680077
Type: single nucleotide variant
Location: chr11:17395258 (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 1442: the abc transporter 2 domain

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

Disease context

maturity-onset diabetes of the young — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hyperinsulinemic hypoglycemia, familial, 1 transient neonatal diabetes mellitus

For MODY (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

ABCC8 p.Glu1442Asp Uncertain significance ★★ ⚠ same residue
ABCC8 p.Glu1442Lys Uncertain significance ★★ ⚠ same residue
ABCC8 p.Glu1442= 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

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-glu1442val (accessed [today's date]).

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