Is ABCC8 p.Arg526Cys (c.1576C>T) pathogenic?

ABCC8 p.Arg526Cys (c.1576C>T) is classified Pathogenic/Likely pathogenic in ABCC8 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-14). AlphaMissense: likely pathogenic (0.9401); Very rare (popmax 0.00254%, nfe); Associated with ABCC8-related disorder.

What condition is associated with ABCC8 p.Arg526Cys (c.1576C>T)?

ABCC8 p.Arg526Cys (c.1576C>T) is associated with ABCC8-related disorder, type 2 diabetes mellitus, hypoglycemia, leucine-induced (ClinVar).

How common is ABCC8 p.Arg526Cys (c.1576C>T) in the general population?

ABCC8 p.Arg526Cys (c.1576C>T) is very rare (popmax 0.00254%, nfe) (gnomAD).

What do computational predictors say about ABCC8 p.Arg526Cys (c.1576C>T)?

AlphaMissense predicts likely pathogenic (score 0.9401) — an in-silico prediction, not a clinical call.

ABCC8 p.Arg526Cys

c.1576C>T · rs751279984 · VCV553752

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.9401 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00254%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ABCC8-related disorder

Computational evidence

Protein change
AlphaMissense	0.9401	likely pathogenic ✓ concordant with ClinVar
REVEL	0.814	moderately pathogenic-leaning
SaProt	LLR -11.54	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 9.9	GERP 1.4, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 84 kb · p 1.4e-12 · regional, not allelic
Overall
CADD	33.0	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 0.00254% European (non-Finnish) · 30/1,180,052 alleles

Filtering AF 0.0018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00156%

Overall 0.00229% 37/1,613,892 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00625%	16,006
European (non-Finnish)grpmax	0.00254%	39,335
Remaining individualsnot grpmax-eligible	0.0016%	62,470
African / African-American	0.00133%	74,914
South Asian	0.0011%	91,066

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg526Cys
Coding: c.1576C>T
MANE Select: NM_000352
dbSNP: rs751279984
Type: single nucleotide variant
Location: chr11:17442774 (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 526: an α-helix; the abc transmembrane type-1 1 domain

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

Disease context

ABCC8-related disorder

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.Arg526His Conflicting classifications of pathogenicity ★ ⚠ same residue
ABCC8 p.Arg526Leu Conflicting classifications of pathogenicity ★ ⚠ 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-arg526cys (accessed [today's date]).

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