Is VCL p.Arg450= (c.1348A>C) pathogenic?

VCL p.Arg450= (c.1348A>C) is classified Benign/Likely benign in VCL (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-02-01). Rare (popmax 0.228%, afr); Associated with Cardiovascular phenotype.

What condition is associated with VCL p.Arg450= (c.1348A>C)?

VCL p.Arg450= (c.1348A>C) is associated with Cardiovascular phenotype, dilated cardiomyopathy 1W, hypertrophic cardiomyopathy 15 (ClinVar).

How common is VCL p.Arg450= (c.1348A>C) in the general population?

VCL p.Arg450= (c.1348A>C) is rare (popmax 0.228%, afr) (gnomAD).

VCL p.Arg450=

c.1348A>C · rs142128712 · VCV178281

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

rare (popmax 0.228%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.8	GERP 2.4, phastCons 1
Overall
CADD	11.41	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.228% African / African-American · 171/75,046 alleles

Filtering AF 0.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.189%

Overall 0.0118% 191/1,614,128 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.228%	439
Remaining individualsnot grpmax-eligible	0.0176%	5,683
Admixed American	0.0117%	8,575
European (non-Finnish)	0.000169%	590,009

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.Arg450=
Coding: c.1348A>C
MANE Select: NM_014000
dbSNP: rs142128712
Type: single nucleotide variant
Location: chr10:74090194 (GRCh38)
Gene constraint: LOEUF 0.461 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.69 · 37 PDB
Residue 450: the 'n-terminal globular head' region; the '3 x 112 aa tandem repeats' region; a turn

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 hypertrophic cardiomyopathy 15

Similar variants

VCL p.Arg450Thr Uncertain significance ★★ ⚠ 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-arg450 (accessed [today's date]).

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