Is ABCC8 p.Asp853Asn (c.2557G>A) pathogenic?

ABCC8 p.Asp853Asn (c.2557G>A) is classified Conflicting classifications of pathogenicity in ABCC8 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2020-06-06). AlphaMissense: likely pathogenic (0.9938); Very rare (popmax 8.47e-05%, nfe); Associated with transient neonatal diabetes mellitus.

What condition is associated with ABCC8 p.Asp853Asn (c.2557G>A)?

ABCC8 p.Asp853Asn (c.2557G>A) is associated with transient neonatal diabetes mellitus, hyperinsulinemic hypoglycemia, familial, 1, maturity-onset diabetes of the young (ClinVar).

How common is ABCC8 p.Asp853Asn (c.2557G>A) in the general population?

ABCC8 p.Asp853Asn (c.2557G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about ABCC8 p.Asp853Asn (c.2557G>A)?

AlphaMissense predicts likely pathogenic (score 0.9938) — an in-silico prediction, not a clinical call.

ABCC8 p.Asp853Asn

c.2557G>A · rs1954765607 · VCV977924

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9938 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

transient neonatal diabetes mellitus

Computational evidence

Protein change
AlphaMissense	0.9938	likely pathogenic · top 6% in ABCC8
REVEL	0.837	moderately pathogenic-leaning
SaProt	LLR -12.81	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 7.6	GERP 2.8, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 84 kb · p 1.4e-12 · regional, not allelic
Overall
CADD	34.0	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 8.47e-05% European (non-Finnish) · 1/1,179,966 alleles

Overall 6.84e-05% 1/1,461,830 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.Asp853Asn
Coding: c.2557G>A
MANE Select: NM_000352
dbSNP: rs1954765607
Type: single nucleotide variant
Location: chr11:17410653 (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 853: the abc transporter 1 domain

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

Disease context

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

Also linked: hyperinsulinemic hypoglycemia, familial, 1 maturity-onset diabetes of the young

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+2T>C Pathogenic/Likely pathogenic ★★ same condition
ABCC8 c.2041-21G>A 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-asp853asn (accessed [today's date]).

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