Is ABCC8 p.Met429Ter (c.1254_1284dup) pathogenic?

ABCC8 p.Met429Ter (c.12541284dup) is classified Pathogenic in ABCC8 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-06-23). Very rare (popmax 0.00153%, nfe); Associated with type 2 diabetes mellitus.

What condition is associated with ABCC8 p.Met429Ter (c.1254_1284dup)?

ABCC8 p.Met429Ter (c.1254_1284dup) is associated with type 2 diabetes mellitus, hypoglycemia, leucine-induced, hyperinsulinemic hypoglycemia, familial, 1 (ClinVar).

How common is ABCC8 p.Met429Ter (c.1254_1284dup) in the general population?

ABCC8 p.Met429Ter (c.1254_1284dup) is very rare (popmax 0.00153%, nfe) (gnomAD).

ABCC8 p.Met429Ter

c.1254_1284dup · rs768951263 · VCV434055

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

Conditions

type 2 diabetes mellitus

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 8 of 39
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.8	GERP 2.3, phastCons 1
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00153% European (non-Finnish) · 18/1,180,036 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00112% 18/1,614,046 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.Met429Ter
Coding: c.1254_1284dup
MANE Select: NM_000352
dbSNP: rs768951263
Type: Duplication
Location: chr11:17448563 (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 429: 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 familial hyperinsulinism diabetes mellitus, permanent neonatal 3

Similar variants

ABCC8 p.Met429Ile Uncertain significance ★ ⚠ same residue
ABCC8 p.Ala286fs Pathogenic/Likely pathogenic ★★ same condition
ABCC8 p.Ser752fs Pathogenic/Likely pathogenic ★★ same condition
ABCC8 p.Val1259fs Pathogenic ★★ same condition
ABCC8 p.Ala146fs Likely pathogenic ★ same condition
ABCC8 p.Asp1192fs Pathogenic ★ same condition
ABCC8 p.Glu1506_Asp1512dup Likely pathogenic ★ same condition
ABCC8 p.Gly1118fs 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-met429ter (accessed [today's date]).

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