Is ABCC8 p.Gln166Lys (c.496C>A) pathogenic?

ABCC8 p.Gln166Lys (c.496C>A) is classified Uncertain significance in ABCC8 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely benign (0.2261); Very rare (popmax 0.000426%, nfe); Associated with transient neonatal diabetes mellitus.

What condition is associated with ABCC8 p.Gln166Lys (c.496C>A)?

ABCC8 p.Gln166Lys (c.496C>A) is associated with transient neonatal diabetes mellitus, maturity-onset diabetes of the young (ClinVar).

How common is ABCC8 p.Gln166Lys (c.496C>A) in the general population?

ABCC8 p.Gln166Lys (c.496C>A) is very rare (popmax 0.000426%, nfe) (gnomAD).

What do computational predictors say about ABCC8 p.Gln166Lys (c.496C>A)?

AlphaMissense predicts likely benign (score 0.2261) — an in-silico prediction, not a clinical call.

ABCC8 p.Gln166Lys

c.496C>A · rs1591896370 · VCV1691261

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2261 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000426%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

transient neonatal diabetes mellitus

Computational evidence

Protein change
AlphaMissense	0.2261	likely benign
REVEL	0.573	indeterminate
SaProt	LLR -8.10	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 8.6	GERP 0.19, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 84 kb · p 1.4e-12 · regional, not allelic
Overall
CADD	24.1	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 0.000426% European (non-Finnish) · 5/1,173,366 alleles

Filtering AF 0.000125% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.1e-05%

Overall 0.000313% 5/1,599,410 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.Gln166Lys
Coding: c.496C>A
MANE Select: NM_000352
dbSNP: rs1591896370
Type: single nucleotide variant
Location: chr11:17463521 (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 166: a β-strand

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: maturity-onset diabetes of the young

Similar variants

ABCC8 p.Gln166Ter Pathogenic/Likely pathogenic ★★ same residue
ABCC8 p.Gln166His Uncertain significance ★ same residue
ABCC8 p.Gln166= Likely benign ★ same residue
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

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-gln166lys (accessed [today's date]).

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