Is ABCC8 p.Arg526His (c.1577G>A) pathogenic?

ABCC8 p.Arg526His (c.1577G>A) is classified Conflicting classifications of pathogenicity in ABCC8 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-08-20). AlphaMissense: likely pathogenic (0.8862); Very rare (popmax 0.00223%, eas); Associated with hyperinsulinemic hypoglycemia, familial, 1.

What condition is associated with ABCC8 p.Arg526His (c.1577G>A)?

ABCC8 p.Arg526His (c.1577G>A) is associated with hyperinsulinemic hypoglycemia, familial, 1, type 2 diabetes mellitus, hypoglycemia, leucine-induced (ClinVar).

How common is ABCC8 p.Arg526His (c.1577G>A) in the general population?

ABCC8 p.Arg526His (c.1577G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ABCC8 p.Arg526His (c.1577G>A)?

AlphaMissense predicts likely pathogenic (score 0.8862) — an in-silico prediction, not a clinical call.

ABCC8 p.Arg526His

c.1577G>A · rs144481621 · VCV2987409

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8862 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hyperinsulinemic hypoglycemia, familial, 1

Computational evidence

Protein change
AlphaMissense	0.8862	likely pathogenic
REVEL	0.862	moderately pathogenic-leaning
SaProt	LLR -9.42	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 6	GERP 2.5, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 84 kb · p 1.4e-12 · regional, not allelic
Overall
CADD	32.0	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 0.00223% East Asian · 1/44,880 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00118% 19/1,613,854 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,880
Admixed American	0.00167%	60,004
Remaining individualsnot grpmax-eligible	0.0016%	62,470
African / African-American	0.00133%	74,924
European (non-Finnish)	0.00127%	78,668

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.Arg526His
Coding: c.1577G>A
MANE Select: NM_000352
dbSNP: rs144481621
Type: single nucleotide variant
Location: chr11:17442773 (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

hyperinsulinemic hypoglycemia, familial, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

ABCC8 p.Arg526Cys Pathogenic/Likely pathogenic ★★ 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-arg526his (accessed [today's date]).

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