Is ABCC8 p.Arg168Cys (c.502C>T) pathogenic?

ABCC8 p.Arg168Cys (c.502C>T) is classified Pathogenic/Likely pathogenic in ABCC8 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-08-19). AlphaMissense: likely pathogenic (0.8734); Ultra-rare (popmax 0.0165%, mid); Associated with Hereditary hyperinsulinism.

What condition is associated with ABCC8 p.Arg168Cys (c.502C>T)?

ABCC8 p.Arg168Cys (c.502C>T) is associated with Hereditary hyperinsulinism, type 2 diabetes mellitus, hypoglycemia, leucine-induced (ClinVar).

How common is ABCC8 p.Arg168Cys (c.502C>T) in the general population?

ABCC8 p.Arg168Cys (c.502C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about ABCC8 p.Arg168Cys (c.502C>T)?

AlphaMissense predicts likely pathogenic (score 0.8734) — an in-silico prediction, not a clinical call.

ABCC8 p.Arg168Cys

c.502C>T · rs756823374 · VCV1459964

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.8734 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hereditary hyperinsulinism

Computational evidence

Protein change
AlphaMissense	0.8734	likely pathogenic ✓ concordant with ClinVar
REVEL	0.96	strongly pathogenic-leaning
SaProt	LLR -8.44	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 84 kb · p 1.4e-12 · regional, not allelic
Overall
CADD	34.0	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 0.0165% Middle Eastern · 1/6,070 alleles

Filtering AF 0.000807% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000653%

Overall 0.00125% 20/1,600,116 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,070
Ashkenazi Jewishnot grpmax-eligible	0.00342%	29,250
Remaining individualsnot grpmax-eligible	0.00161%	62,000
European (non-Finnish)	0.00136%	73,359
South Asian	0.00113%	88,260

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.Arg168Cys
Coding: c.502C>T
MANE Select: NM_000352
dbSNP: rs756823374
Type: single nucleotide variant
Location: chr11:17463515 (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 168: an α-helix

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

Disease context

Hereditary hyperinsulinism

Also linked: type 2 diabetes mellitus hypoglycemia, leucine-induced hyperinsulinemic hypoglycemia, familial, 1 diabetes mellitus, transient neonatal, 2 familial hyperinsulinism diabetes mellitus, permanent neonatal 3

Similar variants

ABCC8 p.Arg168Pro Likely pathogenic ★ ⚠ same residue
ABCC8 p.Arg168= 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

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-arg168cys (accessed [today's date]).

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