Is ACBD4 p.Pro224Leu (c.671C>T) pathogenic?

ACBD4 p.Pro224Leu (c.671C>T) is classified Likely benign in ACBD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-06). AlphaMissense: likely benign (0.0767); Ultra-rare (popmax 0.0865%, nfe).

How common is ACBD4 p.Pro224Leu (c.671C>T) in the general population?

ACBD4 p.Pro224Leu (c.671C>T) is ultra-rare (popmax 0.0865%, nfe) (gnomAD).

What do computational predictors say about ACBD4 p.Pro224Leu (c.671C>T)?

AlphaMissense predicts likely benign (score 0.0767) — an in-silico prediction, not a clinical call.

ACBD4 p.Pro224Leu

c.671C>T · rs369014950 · VCV2355253

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0767 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0865%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0767	likely benign
REVEL	0.032	moderately benign-leaning
SaProt	LLR -7.66	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.1	GERP -4
Regional constraint	o/e 1.02	unconstrained · MANE · 6,861 bp · p 0.72 · regional, not allelic
Overall
CADD	0.02	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 R221W vs ClinVar P224L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0865% European (non-Finnish) · 1,021/1,180,022 alleles

Filtering AF 0.0821% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0803%

Overall 0.0658% 1,061/1,613,372 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0865%	1,156
Remaining individualsnot grpmax-eligible	0.0368%	2,716
African / African-American	0.012%	8,325
South Asian	0.00659%	15,179
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
Admixed American	0.00167%	59,998

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: ACBD4
Protein: p.Pro224Leu
Coding: c.671C>T
MANE Select: NM_001135705
dbSNP: rs369014950
Type: single nucleotide variant
Location: chr17:45139042 (GRCh38)
Gene constraint: LOEUF 1.09 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 65.38 · 1 PDB

Full ACBD4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACBD4 c.*20T>A Uncertain significance ★ same type
ACBD4 c.*27A>G Uncertain significance ★ same type
ACBD4 c.*38T>C Uncertain significance ★ same type
ACBD4 c.*3G>A Uncertain significance ★ same type
ACBD4 c.*51T>G Uncertain significance ★ same type
ACBD4 c.*54G>A Uncertain significance ★ same type
ACBD4 p.Ala282= Uncertain significance ★ same type
ACBD4 p.Ala282Glu 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/acbd4-p-pro224leu (accessed [today's date]).

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