Is ABHD8 p.Ala426Pro (c.1276G>C) pathogenic?

ABHD8 p.Ala426Pro (c.1276G>C) is classified Uncertain significance in ABHD8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-07). AlphaMissense: likely benign (0.0561); Very rare (popmax 0.00017%, nfe).

How common is ABHD8 p.Ala426Pro (c.1276G>C) in the general population?

ABHD8 p.Ala426Pro (c.1276G>C) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about ABHD8 p.Ala426Pro (c.1276G>C)?

AlphaMissense predicts likely benign (score 0.0561) — an in-silico prediction, not a clinical call.

ABHD8 p.Ala426Pro

c.1276G>C · VCV4636345

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0561 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0561	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -4.37	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP 1.4, phastCons 0.55
Regional constraint	o/e 0.76	unconstrained · MANE · 8,424 bp · p 8.1e-06 · regional, not allelic
Overall
CADD	18.19	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 0.00017% European (non-Finnish) · 2/1,179,756 alleles

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

Overall 0.000124% 2/1,612,976 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: ABHD8
Protein: p.Ala426Pro
Coding: c.1276G>C
MANE Select: NM_024527
Type: single nucleotide variant
Location: chr19:17292705 (GRCh38)
Gene constraint: LOEUF 0.664 · pLI 0.25 (gnomAD)
Structure: AlphaFold pLDDT 79.84

Full ABHD8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABHD8 p.Ala20= Benign ★★ same type
ABHD8 p.Ala136Thr Uncertain significance ★ ⚠ same type
ABHD8 p.Ala215Val Uncertain significance ★ ⚠ same type
ABHD8 p.Ala218Val Uncertain significance ★ ⚠ same type
ABHD8 p.Ala236Thr Uncertain significance ★ ⚠ same type
ABHD8 p.Ala319Asp Uncertain significance ★ ⚠ same type
ABHD8 p.Ala319Gly Uncertain significance ★ ⚠ same type
ABHD8 p.Ala63Pro Uncertain significance ★ ⚠ same type

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/abhd8-p-ala426pro (accessed [today's date]).

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