Is ABCC8 p.Arg1352His (c.4055G>A) pathogenic?

ABCC8 p.Arg1352His (c.4055G>A) is classified Conflicting classifications of pathogenicity in ABCC8 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-15). AlphaMissense: ambiguous (0.5512); Very rare (popmax 0.00136%, nfe); Associated with diabetes mellitus, permanent neonatal 3.

What condition is associated with ABCC8 p.Arg1352His (c.4055G>A)?

ABCC8 p.Arg1352His (c.4055G>A) is associated with diabetes mellitus, permanent neonatal 3, type 2 diabetes mellitus, hypoglycemia, leucine-induced (ClinVar).

How common is ABCC8 p.Arg1352His (c.4055G>A) in the general population?

ABCC8 p.Arg1352His (c.4055G>A) is very rare (popmax 0.00136%, nfe) (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.Arg1352His (c.4055G>A)?

AlphaMissense predicts ambiguous (score 0.5512) — an in-silico prediction, not a clinical call.

ABCC8 p.Arg1352His

c.4055G>A · rs28936370 · VCV9098

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

ambiguous

0.5512 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

diabetes mellitus, permanent neonatal 3

Computational evidence

Protein change
AlphaMissense	0.5512	ambiguous
REVEL	0.934	strongly pathogenic-leaning
SaProt	LLR -11.56	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
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	32.0	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 0.00136% European (non-Finnish) · 16/1,180,032 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00109% 16/1,461,874 alleles · very rare

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.Arg1352His
Coding: c.4055G>A
MANE Select: NM_000352
dbSNP: rs28936370
Type: single nucleotide variant
Location: chr11:17396980 (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 1352: a UniProt-annotated variant site (in lih; partially impairs atp-dependent potassium channel function); a UniProt-annotated variant site (in hhf1); the abc transporter 2 domain

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

Disease context

diabetes mellitus, permanent neonatal 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: type 2 diabetes mellitus hypoglycemia, leucine-induced 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.Arg1352Pro Pathogenic/Likely pathogenic ★★ same residue
ABCC8 p.Arg1352Cys 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

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-arg1352his (accessed [today's date]).

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