Is ABHD4 p.Ile85Phe (c.253A>T) pathogenic?

ABHD4 p.Ile85Phe (c.253A>T) is classified Uncertain significance in ABHD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-20). AlphaMissense: likely pathogenic (0.6693); Very rare (popmax 0.00223%, eas).

How common is ABHD4 p.Ile85Phe (c.253A>T) in the general population?

ABHD4 p.Ile85Phe (c.253A>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ABHD4 p.Ile85Phe (c.253A>T)?

AlphaMissense predicts likely pathogenic (score 0.6693) — an in-silico prediction, not a clinical call.

ABHD4 p.Ile85Phe

c.253A>T · VCV3322660

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6693 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6693	likely pathogenic
REVEL	0.278	benign-leaning
SaProt	LLR -8.02	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP -0.5, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 5,265 bp · p 0.02 · regional, not allelic
Overall
CADD	24.0	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 0.00223% East Asian · 1/44,872 alleles

Overall 6.84e-05% 1/1,461,870 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: ABHD4
Protein: p.Ile85Phe
Coding: c.253A>T
MANE Select: NM_022060
Type: single nucleotide variant
Location: chr14:22603530 (GRCh38)
Gene constraint: LOEUF 1.038 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.30
Residue 85: the ab hydrolase-1 domain

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

Similar variants

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
ABHD4 p.Arg21His 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-ile85phe (accessed [today's date]).

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