Is VCL p.Ala469= (c.1407C>T) pathogenic?

VCL p.Ala469= (c.1407C>T) is classified Benign in VCL (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-04). Common (popmax 21.2%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Cardiovascular phenotype.

What condition is associated with VCL p.Ala469= (c.1407C>T)?

VCL p.Ala469= (c.1407C>T) is associated with Cardiovascular phenotype, dilated cardiomyopathy 1W (ClinVar).

VCL p.Ala469=

Q: How common is VCL p.Ala469= (c.1407C>T) in the general population?

VCL p.Ala469= (c.1407C>T) is common (popmax 21.2%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1407C>T · rs2229507 · VCV45579

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

gnomAD v4.1

Common

common (popmax 21.2%, afr) — too common for a highly-penetrant pathogenic allele

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 -0.23	GERP -1.9, phastCons 0.13
Overall
CADD	7.531	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 21.2% African / African-American · 15,870/74,902 alleles

Filtering AF 20.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 20.8%

Overall 1.48% 23,934/1,613,982 alleles · common exomes 14,468/1,461,870 · genomes 9,466/152,112 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	21.2%	5
Middle Eastern	2.08%	48
Ashkenazi Jewishnot grpmax-eligible	2.02%	50
Remaining individualsnot grpmax-eligible	1.92%	52
Admixed American	1.59%	63
European (non-Finnish)	0.408%	245
Amishnot grpmax-eligible	0.33%	303
South Asian	0.311%	322
East Asian	0.107%	935
Finnishnot grpmax-eligible	0.0453%	2,208

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.Ala469=
Coding: c.1407C>T
MANE Select: NM_014000
dbSNP: rs2229507
Type: single nucleotide variant
Location: chr10:74094325 (GRCh38)
Gene constraint: LOEUF 0.461 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.69 · 37 PDB
Residue 469: the 'n-terminal globular head' region; the '3 x 112 aa tandem repeats' 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 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
VCL c.2023-1G>C 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-ala469 (accessed [today's date]).

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