Is ABCC8 p.Lys649= (c.1947G>A) pathogenic?

ABCC8 p.Lys649= (c.1947G>A) is classified Conflicting classifications of pathogenicity in ABCC8 (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-02-04). Common (popmax 28.1%, sas) — too common for a highly-penetrant pathogenic allele; Associated with diabetes mellitus, permanent neonatal 3.

What condition is associated with ABCC8 p.Lys649= (c.1947G>A)?

ABCC8 p.Lys649= (c.1947G>A) is associated with diabetes mellitus, permanent neonatal 3, type 2 diabetes mellitus, hypoglycemia, leucine-induced (ClinVar).

How is Isolated permanent neonatal diabetes mellitus inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

ABCC8 p.Lys649=

Q: How common is ABCC8 p.Lys649= (c.1947G>A) in the general population?

ABCC8 p.Lys649= (c.1947G>A) is common (popmax 28.1%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1947G>A · rs1799858 · VCV157686

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

gnomAD v4.1

Common

common (popmax 28.1%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

diabetes mellitus, permanent neonatal 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.24	GERP -1.2, phastCons 0.97
Overall
CADD	7.36	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 28.1% South Asian · 25,559/91,058 alleles

Filtering AF 27.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 27.7%

Overall 16% 258,896/1,613,742 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	28.1%	4
East Asian	19.9%	5
Finnishnot grpmax-eligible	19.7%	5
Ashkenazi Jewishnot grpmax-eligible	18.7%	5
African / African-American	17.9%	6
Remaining individualsnot grpmax-eligible	16.6%	6
European (non-Finnish)	14.7%	7
Admixed American	13.8%	7
Amishnot grpmax-eligible	11.9%	8
Middle Eastern	11.7%	9

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.Lys649=
Coding: c.1947G>A
MANE Select: NM_000352
dbSNP: rs1799858
Type: single nucleotide variant
Location: chr11:17428382 (GRCh38)
Gene constraint: LOEUF 0.829 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 82.56 · 8 PDB

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

Disease context

diabetes mellitus, permanent neonatal 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

For Isolated permanent neonatal diabetes mellitus (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Antenatal, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

ABCC8 p.Lys649Ter Likely pathogenic ★ 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
ABCC8 c.1817+1G>C 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-lys649 (accessed [today's date]).

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