Is ABHD4 p.Pro178Leu (c.533C>T) pathogenic?

ABHD4 p.Pro178Leu (c.533C>T) is classified Uncertain significance in ABHD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-17). AlphaMissense: ambiguous (0.5244); Ultra-rare (popmax 0.0164%, mid).

How common is ABHD4 p.Pro178Leu (c.533C>T) in the general population?

ABHD4 p.Pro178Leu (c.533C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about ABHD4 p.Pro178Leu (c.533C>T)?

AlphaMissense predicts ambiguous (score 0.5244) — an in-silico prediction, not a clinical call.

ABHD4 p.Pro178Leu

c.533C>T · rs146399735 · VCV3131047

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5244 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Computational evidence

Protein change
AlphaMissense	0.5244	ambiguous
REVEL	0.617	indeterminate
SaProt	LLR -9.71	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 7,212 bp · p 0.74 · regional, not allelic
Overall
CADD	27.6	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00377% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00345%

Overall 0.00397% 64/1,614,092 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Admixed American	0.005%	20,001
European (non-Finnish)	0.00483%	20,703
South Asian	0.00329%	30,363

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: ABHD4
Protein: p.Pro178Leu
Coding: c.533C>T
MANE Select: NM_022060
dbSNP: rs146399735
Type: single nucleotide variant
Location: chr14:22603972 (GRCh38)
Gene constraint: LOEUF 1.038 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.30
Residue 178: the ab hydrolase-1 domain

Full ABHD4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABHD4 p.Pro178Ser Uncertain significance ★ ⚠ same residue
ABHD4 p.Ala230Glu Uncertain significance ★ ⚠ same type
ABHD4 p.Ala2Thr Uncertain significance ★ ⚠ same type
ABHD4 p.Arg115Lys Uncertain significance ★ ⚠ same type
ABHD4 p.Arg132Gln Uncertain significance ★ ⚠ same type
ABHD4 p.Arg185Cys Uncertain significance ★ ⚠ same type
ABHD4 p.Arg185His Uncertain significance ★ ⚠ same type
ABHD4 p.Arg200Cys 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/abhd4-p-pro178leu (accessed [today's date]).

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