Is ABHD4 p.Arg185Cys (c.553C>T) pathogenic?

ABHD4 p.Arg185Cys (c.553C>T) is classified Uncertain significance in ABHD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-27). AlphaMissense: likely benign (0.2145); Ultra-rare (popmax 0.0133%, amr).

How common is ABHD4 p.Arg185Cys (c.553C>T) in the general population?

ABHD4 p.Arg185Cys (c.553C>T) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about ABHD4 p.Arg185Cys (c.553C>T)?

AlphaMissense predicts likely benign (score 0.2145) — an in-silico prediction, not a clinical call.

ABHD4 p.Arg185Cys

c.553C>T · VCV3430471

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2145 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2145	likely benign
REVEL	0.582	indeterminate
SaProt	LLR -6.19	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 7.7	GERP 1.1, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 7,212 bp · p 0.74 · regional, not allelic
Overall
CADD	28.1	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 0.0133% Admixed American · 8/60,028 alleles

Filtering AF 0.00661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.00109% 16/1,461,894 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,504
European (non-Finnish)	0.000678%	147,505

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.Arg185Cys
Coding: c.553C>T
MANE Select: NM_022060
Type: single nucleotide variant
Location: chr14:22603992 (GRCh38)
Gene constraint: LOEUF 1.038 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.30
Residue 185: the ab hydrolase-1 domain

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

Similar variants

ABHD4 p.Arg185His 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.Arg200Cys Uncertain significance ★ ⚠ same type
ABHD4 p.Arg21His Uncertain significance ★ ⚠ same type
ABHD4 p.Arg267Gln 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-arg185cys (accessed [today's date]).

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