Is ABCC8 p.Arg653Gln (c.1958G>A) pathogenic?

ABCC8 p.Arg653Gln (c.1958G>A) is classified Conflicting classifications of pathogenicity in ABCC8 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.089); Rare (popmax 0.397%, sas); Associated with permanent neonatal diabetes mellitus.

What condition is associated with ABCC8 p.Arg653Gln (c.1958G>A)?

ABCC8 p.Arg653Gln (c.1958G>A) is associated with permanent neonatal diabetes mellitus, hyperinsulinemic hypoglycemia, familial, 1, diabetes mellitus, transient neonatal, 2 (ClinVar).

How common is ABCC8 p.Arg653Gln (c.1958G>A) in the general population?

ABCC8 p.Arg653Gln (c.1958G>A) is rare (popmax 0.397%, 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.Arg653Gln (c.1958G>A)?

AlphaMissense predicts likely benign (score 0.089) — an in-silico prediction, not a clinical call.

ABCC8 p.Arg653Gln

c.1958G>A · rs146378237 · VCV303779

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.089 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.397%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

permanent neonatal diabetes mellitus

Computational evidence

Protein change
AlphaMissense	0.089	likely benign
REVEL	0.567	indeterminate
SaProt	LLR -5.75	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 84 kb · p 1.4e-12 · regional, not allelic
Overall
CADD	29.0	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 0.397% South Asian · 362/91,080 alleles

Filtering AF 0.364% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.35%

Overall 0.0258% 417/1,614,096 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.397%	252
Remaining individualsnot grpmax-eligible	0.0368%	2,718
African / African-American	0.0173%	5,773
Middle Eastern	0.0165%	6,058
Admixed American	0.005%	20,012
East Asian	0.00223%	44,878
European (non-Finnish)	0.00119%	84,284

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.Arg653Gln
Coding: c.1958G>A
MANE Select: NM_000352
dbSNP: rs146378237
Type: single nucleotide variant
Location: chr11:17428371 (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: hyperinsulinemic hypoglycemia, familial, 1 diabetes mellitus, transient neonatal, 2

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 p.Arg653Trp 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
ABCC8 c.1817+2T>C 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-arg653gln (accessed [today's date]).

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