Is ACBD5 p.Pro491Leu (c.1472C>T) pathogenic?

ACBD5 p.Pro491Leu (c.1472C>T) is classified Uncertain significance in ACBD5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-12). AlphaMissense: ambiguous (0.4835); Very rare (popmax 0.0039%, nfe).

How common is ACBD5 p.Pro491Leu (c.1472C>T) in the general population?

ACBD5 p.Pro491Leu (c.1472C>T) is very rare (popmax 0.0039%, nfe) (gnomAD).

What do computational predictors say about ACBD5 p.Pro491Leu (c.1472C>T)?

AlphaMissense predicts ambiguous (score 0.4835) — an in-silico prediction, not a clinical call.

ACBD5 p.Pro491Leu

c.1472C>T · rs774247623 · VCV1897628

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4835 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0039%, nfe)

Computational evidence

Protein change
AlphaMissense	0.4835	ambiguous
REVEL	0.616	indeterminate
SaProt	LLR -11.55	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 43 kb · p 0.00076 · regional, not allelic
Overall
CADD	29.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P500L vs ClinVar P491L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0039% European (non-Finnish) · 46/1,179,838 alleles

Filtering AF 0.00299% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00267%

Overall 0.00304% 49/1,613,624 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0039%	25,649
Remaining individualsnot grpmax-eligible	0.0032%	31,240
Finnishnot grpmax-eligible	0.00156%	63,954

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: ACBD5
Protein: p.Pro491Leu
Coding: c.1472C>T
MANE Select: NM_145698
dbSNP: rs774247623
Type: single nucleotide variant
Location: chr10:27204533 (GRCh38)
Gene constraint: LOEUF 0.734 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 57.49 · 1 PDB

Full ACBD5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACBD5 p.Pro491Ser Uncertain significance ★★ ⚠ same residue
ACBD5 p.Arg433Ter Pathogenic/Likely pathogenic ★★ same type
ACBD5 p.Ala182Thr Uncertain significance ★★ ⚠ same type
ACBD5 p.Arg384Trp Uncertain significance ★★ ⚠ same type
ACBD5 p.Arg415Trp Uncertain significance ★★ ⚠ same type
ACBD5 p.Asp429Asn Uncertain significance ★★ ⚠ same type
ACBD5 p.Gln452His Uncertain significance ★★ ⚠ same type
ACBD5 p.Glu312Lys 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/acbd5-p-pro491leu (accessed [today's date]).

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