Is ACOT4 p.Phe367Leu (c.1101C>A) pathogenic?

ACOT4 p.Phe367Leu (c.1101C>A) is classified Uncertain significance in ACOT4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-01). AlphaMissense: likely pathogenic (0.7752); Very rare (popmax 0.00144%, nfe).

How common is ACOT4 p.Phe367Leu (c.1101C>A) in the general population?

ACOT4 p.Phe367Leu (c.1101C>A) is very rare (popmax 0.00144%, nfe) (gnomAD).

What do computational predictors say about ACOT4 p.Phe367Leu (c.1101C>A)?

AlphaMissense predicts likely pathogenic (score 0.7752) — an in-silico prediction, not a clinical call.

ACOT4 p.Phe367Leu

c.1101C>A · VCV4216798

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7752 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00144%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7752	likely pathogenic
REVEL	0.218	benign-leaning
SaProt	LLR -7.00	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 -2.7	GERP -2.4
Regional constraint	o/e 1.03	unconstrained · MANE · 3,691 bp · p 0.48 · regional, not allelic
Overall
CADD	19.03	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 0.00144% European (non-Finnish) · 17/1,179,816 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000718%

Overall 0.00116% 17/1,461,600 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: ACOT4
Protein: p.Phe367Leu
Coding: c.1101C>A
MANE Select: NM_152331
Type: single nucleotide variant
Location: chr14:73595489 (GRCh38)
Gene constraint: LOEUF 1.586 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.47 · 1 PDB
Residue 367: an α-helix

Full ACOT4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACOT4 p.Ala235Gly Uncertain significance ★ ⚠ same type
ACOT4 p.Ala235Thr Uncertain significance ★ ⚠ same type
ACOT4 p.Ala242Ser Uncertain significance ★ ⚠ same type
ACOT4 p.Ala242Val Uncertain significance ★ ⚠ same type
ACOT4 p.Ala372Gly Uncertain significance ★ ⚠ same type
ACOT4 p.Ala48Thr Uncertain significance ★ ⚠ same type
ACOT4 p.Ala65Thr Uncertain significance ★ ⚠ same type
ACOT4 p.Ala65Val 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/acot4-p-phe367leu (accessed [today's date]).

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