Is ABCC8 p.Ala993Thr (c.2977G>A) pathogenic?

ABCC8 p.Ala993Thr (c.2977G>A) is classified Uncertain significance in ABCC8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-09-14). AlphaMissense: likely benign (0.0744); Ultra-rare (popmax 0.012%, afr); Associated with transient neonatal diabetes mellitus.

What condition is associated with ABCC8 p.Ala993Thr (c.2977G>A)?

ABCC8 p.Ala993Thr (c.2977G>A) is associated with transient neonatal diabetes mellitus, hyperinsulinemic hypoglycemia, familial, 1, maturity-onset diabetes of the young (ClinVar).

How common is ABCC8 p.Ala993Thr (c.2977G>A) in the general population?

ABCC8 p.Ala993Thr (c.2977G>A) is ultra-rare (popmax 0.012%, afr) (gnomAD).

What do computational predictors say about ABCC8 p.Ala993Thr (c.2977G>A)?

AlphaMissense predicts likely benign (score 0.0744) — an in-silico prediction, not a clinical call.

ABCC8 p.Ala993Thr

c.2977G>A · rs148342166 · VCV981170

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0744 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

transient neonatal diabetes mellitus

Computational evidence

Protein change
AlphaMissense	0.0744	likely benign
REVEL	0.375	indeterminate
SaProt	LLR -6.15	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
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	20.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.012% African / African-American · 9/75,056 alleles

Filtering AF 0.00622% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00467%

Overall 0.000558% 9/1,613,990 alleles · ultra-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.Ala993Thr
Coding: c.2977G>A
MANE Select: NM_000352
dbSNP: rs148342166
Type: single nucleotide variant
Location: chr11:17407073 (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

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 p.Ala993= Likely benign ★ 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+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-ala993thr (accessed [today's date]).

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