Is VCL p.Pro605Arg (c.1814C>G) pathogenic?

VCL p.Pro605Arg (c.1814C>G) is classified Uncertain significance in VCL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-19). AlphaMissense: likely pathogenic (0.9893); Very rare (popmax 0.000763%, nfe); Associated with hypertrophic cardiomyopathy 15.

What condition is associated with VCL p.Pro605Arg (c.1814C>G)?

VCL p.Pro605Arg (c.1814C>G) is associated with hypertrophic cardiomyopathy 15, dilated cardiomyopathy 1W (ClinVar).

How common is VCL p.Pro605Arg (c.1814C>G) in the general population?

VCL p.Pro605Arg (c.1814C>G) is very rare (popmax 0.000763%, nfe) (gnomAD).

What do computational predictors say about VCL p.Pro605Arg (c.1814C>G)?

AlphaMissense predicts likely pathogenic (score 0.9893) — an in-silico prediction, not a clinical call.

VCL p.Pro605Arg

c.1814C>G · rs960761223 · VCV468812

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9893 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypertrophic cardiomyopathy 15

Computational evidence

Protein change
AlphaMissense	0.9893	likely pathogenic
REVEL	0.822	moderately pathogenic-leaning
SaProt	LLR -17.33	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.7, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 38 kb · p 3e-08 · regional, not allelic
Overall
CADD	27.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000763% European (non-Finnish) · 9/1,179,996 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000558% 9/1,613,986 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.Pro605Arg
Coding: c.1814C>G
MANE Select: NM_014000
dbSNP: rs960761223
Type: single nucleotide variant
Location: chr10:74097274 (GRCh38)
Gene constraint: LOEUF 0.461 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.69 · 37 PDB
Residue 605: 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

hypertrophic cardiomyopathy 15 — 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-pro605arg (accessed [today's date]).

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