Is VCL p.Pro75Leu (c.224C>T) pathogenic?

VCL p.Pro75Leu (c.224C>T) is classified Uncertain significance in VCL (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-10-08). AlphaMissense: likely pathogenic (0.68); Ultra-rare (popmax 0.0157%, eas); Associated with Cardiovascular phenotype.

What condition is associated with VCL p.Pro75Leu (c.224C>T)?

VCL p.Pro75Leu (c.224C>T) is associated with Cardiovascular phenotype, dilated cardiomyopathy 1W (ClinVar).

How common is VCL p.Pro75Leu (c.224C>T) in the general population?

VCL p.Pro75Leu (c.224C>T) is ultra-rare (popmax 0.0157%, eas) (gnomAD).

What do computational predictors say about VCL p.Pro75Leu (c.224C>T)?

AlphaMissense predicts likely pathogenic (score 0.68) — an in-silico prediction, not a clinical call.

VCL p.Pro75Leu

c.224C>T · rs373830664 · VCV202151

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.68 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0157%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.68	likely pathogenic
REVEL	0.241	benign-leaning
SaProt	LLR -12.69	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 73 kb · p 0.00039 · regional, not allelic
Overall
CADD	28.7	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 0.0157% East Asian · 7/44,718 alleles

Filtering AF 0.00728% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00516%

Overall 0.000744% 12/1,613,088 alleles · ultra-rare exomes 9/1,460,946 · genomes 3/152,142 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0157%	6,388
Remaining individualsnot grpmax-eligible	0.0048%	20,821
South Asian	0.0022%	45,522

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: VCL
Protein: p.Pro75Leu
Coding: c.224C>T
MANE Select: NM_014000
dbSNP: rs373830664
Type: single nucleotide variant
Location: chr10:74043138 (GRCh38)
Gene constraint: LOEUF 0.461 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.69 · 37 PDB
Residue 75: the 'n-terminal globular head' region; an α-helix

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dilated cardiomyopathy 1W

Similar variants

VCL p.Pro75= Likely benign ★★ same residue
VCL c.1176+4G>C Uncertain significance ★★ same condition
VCL c.1352+5G>A Uncertain significance ★★ same condition
VCL c.1543+1G>T Uncertain significance ★★ same condition
VCL c.1543+4A>G Uncertain significance ★★ same condition
VCL c.1743+6A>G Uncertain significance ★★ same condition
VCL c.1744-1G>T Uncertain significance ★★ same condition
VCL c.2022+5G>T 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/vcl-p-pro75leu (accessed [today's date]).

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