Is ABCC8 p.Pro753= (c.2259A>G) pathogenic?

ABCC8 p.Pro753= (c.2259A>G) is classified Conflicting classifications of pathogenicity in ABCC8 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-03-18). Very rare (popmax 0.00017%, nfe); Associated with maturity-onset diabetes of the young.

What condition is associated with ABCC8 p.Pro753= (c.2259A>G)?

ABCC8 p.Pro753= (c.2259A>G) is associated with maturity-onset diabetes of the young, transient neonatal diabetes mellitus (ClinVar).

How common is ABCC8 p.Pro753= (c.2259A>G) in the general population?

ABCC8 p.Pro753= (c.2259A>G) is very rare (popmax 0.00017%, nfe) (gnomAD).

How is MODY inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

ABCC8 p.Pro753=

c.2259A>G · rs1955020359 · VCV990405

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Conditions

maturity-onset diabetes of the young

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 -5	GERP -3.6
Overall
CADD	5.134	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,048 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,458,440 alleles · very rare

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.Pro753=
Coding: c.2259A>G
MANE Select: NM_000352
dbSNP: rs1955020359
Type: single nucleotide variant
Location: chr11:17415336 (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 753: the abc transporter 1 domain

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

Disease context

maturity-onset diabetes of the young — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: transient neonatal diabetes mellitus

For MODY (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

ABCC8 c.2116+2T>C Pathogenic/Likely pathogenic ★★ same condition
ABCC8 c.3868-1G>A Pathogenic/Likely pathogenic ★★ same condition
ABCC8 c.3989-9G>A Pathogenic ★★ same condition
ABCC8 c.4308-2A>G Pathogenic/Likely pathogenic ★★ same condition
ABCC8 p.Arg1379His Pathogenic/Likely pathogenic ★★ same condition
ABCC8 p.Arg1538Gln Pathogenic/Likely pathogenic ★★ same condition
ABCC8 p.Gly228Asp Pathogenic/Likely pathogenic ★★ same condition
ABCC8 p.Gly716Ser 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-pro753 (accessed [today's date]).

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