Is ABCC8 p.Glu746Lys (c.2236G>A) pathogenic?

ABCC8 p.Glu746Lys (c.2236G>A) is classified Uncertain significance in ABCC8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-12-15). AlphaMissense: likely benign (0.1027); Very rare (popmax 0.00167%, amr); Associated with maturity-onset diabetes of the young.

What condition is associated with ABCC8 p.Glu746Lys (c.2236G>A)?

ABCC8 p.Glu746Lys (c.2236G>A) is associated with maturity-onset diabetes of the young, transient neonatal diabetes mellitus (ClinVar).

How common is ABCC8 p.Glu746Lys (c.2236G>A) in the general population?

ABCC8 p.Glu746Lys (c.2236G>A) is very rare (popmax 0.00167%, amr) (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.Glu746Lys (c.2236G>A)?

AlphaMissense predicts likely benign (score 0.1027) — an in-silico prediction, not a clinical call.

ABCC8 p.Glu746Lys

c.2236G>A · rs753296261 · VCV1690303

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1027 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

maturity-onset diabetes of the young

Computational evidence

Protein change
AlphaMissense	0.1027	likely benign
REVEL	0.602	indeterminate
SaProt	LLR -7.07	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.65 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.7	GERP 2.2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 84 kb · p 1.4e-12 · regional, not allelic
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,754 alleles

Filtering AF 0.00036% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000261%

Overall 0.000756% 11/1,455,316 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,754
Remaining individualsnot grpmax-eligible	0.00161%	62,118
European (non-Finnish)	0.000765%	130,635

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.Glu746Lys
Coding: c.2236G>A
MANE Select: NM_000352
dbSNP: rs753296261
Type: single nucleotide variant
Location: chr11:17416949 (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 746: the abc transporter 1 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: 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.Glu746Ter Pathogenic/Likely pathogenic ★★ same residue
ABCC8 p.Glu746Asp Uncertain significance ★ ⚠ same residue
ABCC8 c.2116+2T>C Pathogenic/Likely pathogenic ★★ same condition
ABCC8 c.3868-1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCC8 c.3989-9G>A Pathogenic ★★ same condition
ABCC8 c.4308-2A>G Pathogenic/Likely pathogenic ★★ same condition
ABCC8 p.Arg1379His Pathogenic/Likely pathogenic ★★ same condition
ABCC8 p.Arg1538Gln 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-glu746lys (accessed [today's date]).

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