Is ACBD5 p.Leu499Pro (c.1496T>C) pathogenic?

ACBD5 p.Leu499Pro (c.1496T>C) is classified Uncertain significance in ACBD5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-12). AlphaMissense: likely pathogenic (0.9226); Very rare (popmax 0.000339%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ACBD5 p.Leu499Pro (c.1496T>C)?

ACBD5 p.Leu499Pro (c.1496T>C) is associated with Inborn genetic diseases (ClinVar).

How common is ACBD5 p.Leu499Pro (c.1496T>C) in the general population?

ACBD5 p.Leu499Pro (c.1496T>C) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about ACBD5 p.Leu499Pro (c.1496T>C)?

AlphaMissense predicts likely pathogenic (score 0.9226) — an in-silico prediction, not a clinical call.

ACBD5 p.Leu499Pro

c.1496T>C · rs2540393631 · VCV1930390

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9226 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9226	likely pathogenic · top 10% in ACBD5
REVEL	0.543	indeterminate
SaProt	LLR -14.80	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.5, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 43 kb · p 0.00076 · regional, not allelic
Overall
CADD	27.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM L508P vs ClinVar L499P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,994 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,614,148 alleles · very rare exomes 4/1,461,782 · genomes 0/152,366 · joint denominator

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.Leu499Pro
Coding: c.1496T>C
MANE Select: NM_145698
dbSNP: rs2540393631
Type: single nucleotide variant
Location: chr10:27204509 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ACBD5 p.Ala182Thr Uncertain significance ★★ ⚠ same condition
ACBD5 p.Arg384Trp Uncertain significance ★★ ⚠ same condition
ACBD5 p.Arg415Trp Uncertain significance ★★ ⚠ same condition
ACBD5 p.Asp429Asn Uncertain significance ★★ ⚠ same condition
ACBD5 p.Gln452His Uncertain significance ★★ ⚠ same condition
ACBD5 p.Glu312Lys Uncertain significance ★★ ⚠ same condition
ACBD5 p.Glu493Lys Uncertain significance ★★ ⚠ same condition
ACBD5 p.Gly180Asp Uncertain significance ★★ ⚠ same condition

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-leu499pro (accessed [today's date]).

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