Is ABCC8 p.Arg1379Ser (c.4135C>A) pathogenic?

ABCC8 p.Arg1379Ser (c.4135C>A) is classified Uncertain significance in ABCC8 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-06-10). AlphaMissense: likely pathogenic (0.9887); Very rare (popmax 0.00881%, amr); Associated with type 2 diabetes mellitus.

What condition is associated with ABCC8 p.Arg1379Ser (c.4135C>A)?

ABCC8 p.Arg1379Ser (c.4135C>A) is associated with type 2 diabetes mellitus, hypoglycemia, leucine-induced, hyperinsulinemic hypoglycemia, familial, 1 (ClinVar).

How common is ABCC8 p.Arg1379Ser (c.4135C>A) in the general population?

ABCC8 p.Arg1379Ser (c.4135C>A) is very rare (popmax 0.00881%, amr) (gnomAD).

What do computational predictors say about ABCC8 p.Arg1379Ser (c.4135C>A)?

AlphaMissense predicts likely pathogenic (score 0.9887) — an in-silico prediction, not a clinical call.

ABCC8 p.Arg1379Ser

c.4135C>A · rs137852673 · VCV35614

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9887 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00881%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

type 2 diabetes mellitus

Computational evidence

Protein change
AlphaMissense	0.9887	likely pathogenic · top 9% in ABCC8
REVEL	0.975	strongly pathogenic-leaning
SaProt	LLR -10.90	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 84 kb · p 1.4e-12 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00881% Admixed American · 5/56,750 alleles

Filtering AF 0.00341% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00217%

Overall 0.000315% 5/1,585,140 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.Arg1379Ser
Coding: c.4135C>A
MANE Select: NM_000352
dbSNP: rs137852673
Type: single nucleotide variant
Location: chr11:17395915 (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 1379: a UniProt-annotated variant site (in tndm2; likely pathogenic); a UniProt-annotated variant site (in mody12; likely pathogenic); 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 monogenic diabetes diabetes mellitus, permanent neonatal 3

Similar variants

ABCC8 p.Arg1379Cys Pathogenic/Likely pathogenic ★★ same residue
ABCC8 p.Arg1379His Pathogenic/Likely pathogenic ★★ same residue
ABCC8 p.Arg1379Leu Pathogenic/Likely pathogenic ★★ same residue
ABCC8 p.Arg1379= 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

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-arg1379ser (accessed [today's date]).

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