Is ABHD2 p.Arg254Gln (c.761G>A) pathogenic?

ABHD2 p.Arg254Gln (c.761G>A) is classified Uncertain significance in ABHD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-31). AlphaMissense: likely pathogenic (0.9511); Very rare (popmax 0.000424%, nfe).

How common is ABHD2 p.Arg254Gln (c.761G>A) in the general population?

ABHD2 p.Arg254Gln (c.761G>A) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about ABHD2 p.Arg254Gln (c.761G>A)?

AlphaMissense predicts likely pathogenic (score 0.9511) — an in-silico prediction, not a clinical call.

ABHD2 p.Arg254Gln

c.761G>A · VCV4163691

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9511 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9511	likely pathogenic
REVEL	0.585	indeterminate
SaProt	LLR -9.44	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.6, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 79 kb · p 5.1e-10 · regional, not allelic
Overall
CADD	33.0	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 0.000424% European (non-Finnish) · 5/1,180,016 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00041% 6/1,461,864 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	64,010
European (non-Finnish)grpmax	0.000424%	236,003

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ABHD2
Protein: p.Arg254Gln
Coding: c.761G>A
MANE Select: NM_152924
Type: single nucleotide variant
Location: chr15:89185462 (GRCh38)
Gene constraint: LOEUF 0.57 · pLI 0.55 (gnomAD)
Structure: AlphaFold pLDDT 91.06
Residue 254: the ab hydrolase-1 domain

Full ABHD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABHD2 p.His312= Benign ★★ same type
ABHD2 p.Tyr400= Benign ★★ same type
ABHD2 p.Val420= Benign ★★ same type
ABHD2 p.Ala222Gly Uncertain significance ★ ⚠ same type
ABHD2 p.Ala274Thr Uncertain significance ★ ⚠ same type
ABHD2 p.Arg175Cys Uncertain significance ★ ⚠ same type
ABHD2 p.Arg293Gln Uncertain significance ★ ⚠ same type
ABHD2 p.Arg328Gln 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/abhd2-p-arg254gln (accessed [today's date]).

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