Is ABCC8 p.Val1364Phe (c.4090G>T) pathogenic?

ABCC8 p.Val1364Phe (c.4090G>T) is classified Conflicting classifications of pathogenicity in ABCC8 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-10-24). AlphaMissense: likely pathogenic (0.6822); Very rare (popmax 0.00195%, nfe); Associated with type 2 diabetes mellitus.

What condition is associated with ABCC8 p.Val1364Phe (c.4090G>T)?

ABCC8 p.Val1364Phe (c.4090G>T) is associated with type 2 diabetes mellitus, hypoglycemia, leucine-induced, hyperinsulinemic hypoglycemia, familial, 1 (ClinVar).

How common is ABCC8 p.Val1364Phe (c.4090G>T) in the general population?

ABCC8 p.Val1364Phe (c.4090G>T) is very rare (popmax 0.00195%, nfe) (gnomAD).

What do computational predictors say about ABCC8 p.Val1364Phe (c.4090G>T)?

AlphaMissense predicts likely pathogenic (score 0.6822) — an in-silico prediction, not a clinical call.

ABCC8 p.Val1364Phe

c.4090G>T · rs138642224 · VCV1684260

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.6822 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00195%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

type 2 diabetes mellitus

Computational evidence

Protein change
AlphaMissense	0.6822	likely pathogenic
REVEL	0.838	moderately pathogenic-leaning
SaProt	LLR -9.27	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 6	GERP 2.7, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 84 kb · p 1.4e-12 · regional, not allelic
Overall
CADD	24.5	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 0.00195% European (non-Finnish) · 23/1,180,030 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00155% 25/1,614,076 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00195%	51,306
Remaining individualsnot grpmax-eligible	0.0016%	62,484
African / African-American	0.00133%	74,930

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.Val1364Phe
Coding: c.4090G>T
MANE Select: NM_000352
dbSNP: rs138642224
Type: single nucleotide variant
Location: chr11:17396945 (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 1364: a β-strand; the abc transporter 2 domain

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

Disease context

type 2 diabetes mellitus — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

ABCC8 p.Val1364Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
ABCC8 p.Val1364= 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

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-val1364phe (accessed [today's date]).

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