Is VCL p.Val658Ala (c.1973T>C) pathogenic?

VCL p.Val658Ala (c.1973T>C) is classified Conflicting classifications of pathogenicity in VCL (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-02-03). AlphaMissense: ambiguous (0.4383); Rare (popmax 0.303%, sas); Associated with dilated cardiomyopathy.

What condition is associated with VCL p.Val658Ala (c.1973T>C)?

VCL p.Val658Ala (c.1973T>C) is associated with dilated cardiomyopathy, dilated cardiomyopathy 1W (ClinVar).

How common is VCL p.Val658Ala (c.1973T>C) in the general population?

VCL p.Val658Ala (c.1973T>C) is rare (popmax 0.303%, sas) (gnomAD).

What do computational predictors say about VCL p.Val658Ala (c.1973T>C)?

AlphaMissense predicts ambiguous (score 0.4383) — an in-silico prediction, not a clinical call.

VCL p.Val658Ala

c.1973T>C · rs372691803 · VCV179606

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.4383 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.303%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

dilated cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.4383	ambiguous
REVEL	0.201	benign-leaning
SaProt	LLR -6.73	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.8, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 38 kb · p 3e-08 · regional, not allelic
Overall
CADD	27.1	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 0.303% South Asian · 276/91,046 alleles

Filtering AF 0.274% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.262%

Overall 0.0177% 285/1,613,824 alleles · rare exomes 270/1,461,612 · genomes 15/152,212 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.303%	330
Middle Eastern	0.0165%	6,056
Remaining individualsnot grpmax-eligible	0.0128%	7,811

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.Val658Ala
Coding: c.1973T>C
MANE Select: NM_014000
dbSNP: rs372691803
Type: single nucleotide variant
Location: chr10:74101048 (GRCh38)
Gene constraint: LOEUF 0.461 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.69 · 37 PDB
Residue 658: 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

dilated cardiomyopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dilated cardiomyopathy 1W

Similar variants

VCL p.Val658Met 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-val658ala (accessed [today's date]).

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