Is ABCC8 p.Glu628Lys (c.1882G>A) pathogenic?

ABCC8 p.Glu628Lys (c.1882G>A) is classified Uncertain significance in ABCC8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-01). AlphaMissense: likely benign (0.0778); Ultra-rare (popmax 0.0154%, sas); Associated with permanent neonatal diabetes mellitus.

What condition is associated with ABCC8 p.Glu628Lys (c.1882G>A)?

ABCC8 p.Glu628Lys (c.1882G>A) is associated with permanent neonatal diabetes mellitus, maturity-onset diabetes of the young, transient neonatal diabetes mellitus (ClinVar).

How common is ABCC8 p.Glu628Lys (c.1882G>A) in the general population?

ABCC8 p.Glu628Lys (c.1882G>A) is ultra-rare (popmax 0.0154%, sas) (gnomAD).

How is Isolated permanent neonatal diabetes mellitus inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about ABCC8 p.Glu628Lys (c.1882G>A)?

AlphaMissense predicts likely benign (score 0.0778) — an in-silico prediction, not a clinical call.

ABCC8 p.Glu628Lys

c.1882G>A · rs565662182 · VCV592095

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0778 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0154%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

permanent neonatal diabetes mellitus

Computational evidence

Protein change
AlphaMissense	0.0778	likely benign
REVEL	0.391	indeterminate
SaProt	LLR -6.28	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.21	acceptor loss, 34 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 84 kb · p 1.4e-12 · regional, not allelic
Overall
CADD	20.8	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 0.0154% South Asian · 14/91,092 alleles

Filtering AF 0.00919% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00735%

Overall 0.00155% 25/1,614,122 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0154%	6,507
Remaining individualsnot grpmax-eligible	0.0032%	31,255
African / African-American	0.00266%	37,532
Admixed American	0.00167%	60,030
European (non-Finnish)	0.000508%	196,672

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.Glu628Lys
Coding: c.1882G>A
MANE Select: NM_000352
dbSNP: rs565662182
Type: single nucleotide variant
Location: chr11:17428606 (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

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

Also linked: maturity-onset diabetes of the young transient neonatal diabetes mellitus

For Isolated permanent neonatal diabetes mellitus (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Antenatal, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

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.Arg1182Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
ABCC8 p.Arg1379Cys 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-glu628lys (accessed [today's date]).

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