Is ABCC8 p.Arg519Cys (c.1555C>T) pathogenic?

ABCC8 p.Arg519Cys (c.1555C>T) is classified Conflicting classifications of pathogenicity in ABCC8 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-21). AlphaMissense: likely benign (0.0609); Ultra-rare (popmax 0.0154%, sas); Associated with type 2 diabetes mellitus.

What condition is associated with ABCC8 p.Arg519Cys (c.1555C>T)?

ABCC8 p.Arg519Cys (c.1555C>T) is associated with type 2 diabetes mellitus, hypoglycemia, leucine-induced, hyperinsulinemic hypoglycemia, familial, 1 (ClinVar).

How common is ABCC8 p.Arg519Cys (c.1555C>T) in the general population?

ABCC8 p.Arg519Cys (c.1555C>T) is ultra-rare (popmax 0.0154%, sas) (gnomAD).

What do computational predictors say about ABCC8 p.Arg519Cys (c.1555C>T)?

AlphaMissense predicts likely benign (score 0.0609) — an in-silico prediction, not a clinical call.

ABCC8 p.Arg519Cys

c.1555C>T · rs1057467571 · VCV2150257

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0609 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0154%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

type 2 diabetes mellitus

Computational evidence

Protein change
AlphaMissense	0.0609	likely benign
REVEL	0.215	benign-leaning
SaProt	LLR -9.27	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.48	GERP -4.9, phastCons 0.96
Regional constraint	o/e 0.84	unconstrained · MANE · 84 kb · p 1.4e-12 · regional, not allelic
Overall
CADD	18.59	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 0.0154% South Asian · 14/91,056 alleles

Filtering AF 0.0092% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00735%

Overall 0.00486% 71/1,461,802 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0154%	6,504
Admixed American	0.015%	6,670
East Asian	0.00891%	11,218
Remaining individualsnot grpmax-eligible	0.0064%	15,625
European (non-Finnish)	0.00322%	31,054
African / African-American	0.00267%	37,519

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.Arg519Cys
Coding: c.1555C>T
MANE Select: NM_000352
dbSNP: rs1057467571
Type: single nucleotide variant
Location: chr11:17442795 (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 519: 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

type 2 diabetes mellitus — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

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+1G>C 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-arg519cys (accessed [today's date]).

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