Is VCL p.Arg993Cys (c.2977C>T) pathogenic?

VCL p.Arg993Cys (c.2977C>T) is classified Uncertain significance in VCL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-10). AlphaMissense: likely pathogenic (0.8081); Very rare (popmax 0.000169%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with VCL p.Arg993Cys (c.2977C>T)?

VCL p.Arg993Cys (c.2977C>T) is associated with Cardiovascular phenotype, dilated cardiomyopathy 1W (ClinVar).

How common is VCL p.Arg993Cys (c.2977C>T) in the general population?

VCL p.Arg993Cys (c.2977C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about VCL p.Arg993Cys (c.2977C>T)?

AlphaMissense predicts likely pathogenic (score 0.8081) — an in-silico prediction, not a clinical call.

VCL p.Arg993Cys

c.2977C>T · rs1591719960 · VCV1800805

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8081 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.8081	likely pathogenic
REVEL	0.327	indeterminate
SaProt	LLR -7.56	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.7, phastCons 1
Regional constraint	o/e 0.45	unconstrained · MANE · 6,073 bp · p 2.6e-15 · regional, not allelic
Overall
CADD	33.0	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 0.000169% European (non-Finnish) · 2/1,180,014 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,606 alleles · very rare

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.Arg993Cys
Coding: c.2977C>T
MANE Select: NM_014000
dbSNP: rs1591719960
Type: single nucleotide variant
Location: chr10:74114211 (GRCh38)
Gene constraint: LOEUF 0.461 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.69 · 37 PDB
Residue 993: the 'c-terminal tail' 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.Arg993His Uncertain significance ★ same residue
VCL p.Arg993Leu 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

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-arg993cys (accessed [today's date]).

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