Is ABCC8 p.Ser1382Arg (c.4146T>G) pathogenic?

ABCC8 p.Ser1382Arg (c.4146T>G) is classified Likely pathogenic in ABCC8 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-04-24). AlphaMissense: likely pathogenic (0.9975); Absent from gnomAD v4.1; Associated with Hereditary hyperinsulinism.

What condition is associated with ABCC8 p.Ser1382Arg (c.4146T>G)?

ABCC8 p.Ser1382Arg (c.4146T>G) is associated with Hereditary hyperinsulinism, hyperinsulinemic hypoglycemia, familial, 1 (ClinVar).

How common is ABCC8 p.Ser1382Arg (c.4146T>G) in the general population?

ABCC8 p.Ser1382Arg (c.4146T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ABCC8 p.Ser1382Arg (c.4146T>G)?

AlphaMissense predicts likely pathogenic (score 0.9975) — an in-silico prediction, not a clinical call.

ABCC8 p.Ser1382Arg

c.4146T>G · rs886039877 · VCV265990

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9975 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hereditary hyperinsulinism

Computational evidence

Protein change
AlphaMissense	0.9975	likely pathogenic ✓ concordant with ClinVar · top 2% in ABCC8
REVEL	0.789	moderately pathogenic-leaning
SaProt	LLR -14.57	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 -0.097	GERP -4.8, phastCons 0.008
Regional constraint	o/e 0.84	unconstrained · MANE · 84 kb · p 1.4e-12 · regional, not allelic
Overall
CADD	22.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ABCC8
Protein: p.Ser1382Arg
Coding: c.4146T>G
MANE Select: NM_000352
dbSNP: rs886039877
Type: single nucleotide variant
Location: chr11:17395904 (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 1382: the abc transporter 2 domain

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

Disease context

Hereditary hyperinsulinism

Also linked: hyperinsulinemic hypoglycemia, familial, 1

Similar variants

ABCC8 p.Ser1382= 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
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-ser1382arg (accessed [today's date]).

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