Is ABHD5 p.Trp138Arg (c.412T>C) pathogenic?

ABHD5 p.Trp138Arg (c.412T>C) is classified Uncertain significance in ABHD5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-25). AlphaMissense: likely pathogenic (0.9979); Very rare (popmax 0.00134%, afr); Associated with Inborn genetic diseases.

What condition is associated with ABHD5 p.Trp138Arg (c.412T>C)?

ABHD5 p.Trp138Arg (c.412T>C) is associated with Inborn genetic diseases (ClinVar).

How common is ABHD5 p.Trp138Arg (c.412T>C) in the general population?

ABHD5 p.Trp138Arg (c.412T>C) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about ABHD5 p.Trp138Arg (c.412T>C)?

AlphaMissense predicts likely pathogenic (score 0.9979) — an in-silico prediction, not a clinical call.

ABHD5 p.Trp138Arg

c.412T>C · rs1282035088 · VCV2299362

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9979 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9979	likely pathogenic · top 1% in ABHD5
REVEL	0.787	moderately pathogenic-leaning
SaProt	LLR -10.34	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.7, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 28 kb · p 0.24 · regional, not allelic
Overall
CADD	29.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00134% African / African-American · 1/74,884 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,613,960 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,884
European (non-Finnish)	0.000254%	393,335

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: ABHD5
Protein: p.Trp138Arg
Coding: c.412T>C
MANE Select: NM_016006
dbSNP: rs1282035088
Type: single nucleotide variant
Location: chr3:43702493 (GRCh38)
Gene constraint: LOEUF 0.922 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.62
Residue 138: the ab hydrolase-1 domain

Full ABHD5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ABHD5 p.Asp12Asn Uncertain significance ★★ ⚠ same condition
ABHD5 p.Cys140Gly Uncertain significance ★★ ⚠ same condition
ABHD5 p.Glu133Asp Uncertain significance ★★ ⚠ same condition
ABHD5 p.Glu5Ala Uncertain significance ★★ ⚠ same condition
ABHD5 p.Ile320Thr Uncertain significance ★★ ⚠ same condition
ABHD5 p.Leu214Ile Uncertain significance ★★ ⚠ same condition
ABHD5 p.Lys342Arg Uncertain significance ★★ ⚠ same condition
ABHD5 p.Pro118Thr Uncertain significance ★★ ⚠ 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/abhd5-p-trp138arg (accessed [today's date]).

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