Is ABCC8 p.Arg918Ser (c.2754G>T) pathogenic?

ABCC8 p.Arg918Ser (c.2754G>T) is classified Uncertain significance in ABCC8 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-04-18). AlphaMissense: likely benign (0.2527); Very rare (popmax 0.0011%, sas); Associated with Hereditary hyperinsulinism.

What condition is associated with ABCC8 p.Arg918Ser (c.2754G>T)?

ABCC8 p.Arg918Ser (c.2754G>T) is associated with Hereditary hyperinsulinism (ClinVar).

How common is ABCC8 p.Arg918Ser (c.2754G>T) in the general population?

ABCC8 p.Arg918Ser (c.2754G>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about ABCC8 p.Arg918Ser (c.2754G>T)?

AlphaMissense predicts likely benign (score 0.2527) — an in-silico prediction, not a clinical call.

ABCC8 p.Arg918Ser

c.2754G>T · VCV4058809

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2527 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Hereditary hyperinsulinism

Computational evidence

Protein change
AlphaMissense	0.2527	likely benign
REVEL	0.426	indeterminate
SaProt	LLR -5.57	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 1.1	GERP -0.4, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 84 kb · p 1.4e-12 · regional, not allelic
Overall
CADD	21.7	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 0.0011% South Asian · 1/91,074 alleles

Overall 6.84e-05% 1/1,461,558 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.Arg918Ser
Coding: c.2754G>T
MANE Select: NM_000352
Type: single nucleotide variant
Location: chr11:17408458 (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 918: an α-helix; the abc transporter 1 domain

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

Disease context

Hereditary hyperinsulinism

Similar variants

ABCC8 p.Arg918Lys Uncertain significance ★★ ⚠ same residue
ABCC8 p.Arg918= 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.2116+2T>C Pathogenic/Likely pathogenic ★★ same condition
ABCC8 c.2117-1G>A Pathogenic ★★ same condition
ABCC8 c.2475+2T>A Likely pathogenic ★★ same condition
ABCC8 c.3988+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-arg918ser (accessed [today's date]).

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