Is ABHD1 p.Arg375His (c.1124G>A) pathogenic?

ABHD1 p.Arg375His (c.1124G>A) is classified Uncertain significance in ABHD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-17). AlphaMissense: likely benign (0.0952); Very rare (popmax 0.00178%, nfe).

How common is ABHD1 p.Arg375His (c.1124G>A) in the general population?

ABHD1 p.Arg375His (c.1124G>A) is very rare (popmax 0.00178%, nfe) (gnomAD).

What do computational predictors say about ABHD1 p.Arg375His (c.1124G>A)?

AlphaMissense predicts likely benign (score 0.0952) — an in-silico prediction, not a clinical call.

ABHD1 p.Arg375His

c.1124G>A · VCV4831877

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0952 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00178%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0952	likely benign
REVEL	0.398	indeterminate
SaProt	LLR -9.31	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 4.3	GERP 1.5, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 6,792 bp · p 0.038 · regional, not allelic
Overall
CADD	23.7	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 0.00178% European (non-Finnish) · 21/1,180,028 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.00144% 21/1,461,856 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: ABHD1
Protein: p.Arg375His
Coding: c.1124G>A
MANE Select: NM_032604
Type: single nucleotide variant
Location: chr2:27130650 (GRCh38)
Gene constraint: LOEUF 1.359 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.75

Full ABHD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABHD1 p.Arg375Cys Uncertain significance ★ ⚠ same residue
ABHD1 p.Ala154Thr Uncertain significance ★ ⚠ same type
ABHD1 p.Ala172Thr Uncertain significance ★ ⚠ same type
ABHD1 p.Ala326Glu Uncertain significance ★ ⚠ same type
ABHD1 p.Ala336Val Uncertain significance ★ ⚠ same type
ABHD1 p.Ala349Val Uncertain significance ★ ⚠ same type
ABHD1 p.Ala381Thr Uncertain significance ★ ⚠ same type
ABHD1 p.Ala50Val 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/abhd1-p-arg375his (accessed [today's date]).

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