Is VCL p.Ser600Arg (c.1798A>C) pathogenic?

VCL p.Ser600Arg (c.1798A>C) is classified Uncertain significance in VCL (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-02). AlphaMissense: likely pathogenic (0.9979); Very rare (popmax 0.00133%, afr); Associated with cardiomyopathy.

What condition is associated with VCL p.Ser600Arg (c.1798A>C)?

VCL p.Ser600Arg (c.1798A>C) is associated with cardiomyopathy, dilated cardiomyopathy 1W (ClinVar).

How common is VCL p.Ser600Arg (c.1798A>C) in the general population?

VCL p.Ser600Arg (c.1798A>C) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about VCL p.Ser600Arg (c.1798A>C)?

AlphaMissense predicts likely pathogenic (score 0.9979) — an in-silico prediction, not a clinical call.

VCL p.Ser600Arg

c.1798A>C · rs397517236 · VCV45591

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9979 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.9979	likely pathogenic · top 5% in VCL
REVEL	0.442	indeterminate
SaProt	LLR -10.45	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.7, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 38 kb · p 3e-08 · regional, not allelic
Overall
CADD	26.3	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 0.00133% African / African-American · 1/75,070 alleles

Overall 6.2e-05% 1/1,614,154 alleles · very rare exomes 1/1,461,786 · genomes 0/152,368 · joint denominator

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.Ser600Arg
Coding: c.1798A>C
MANE Select: NM_014000
dbSNP: rs397517236
Type: single nucleotide variant
Location: chr10:74097258 (GRCh38)
Gene constraint: LOEUF 0.461 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.69 · 37 PDB
Residue 600: a modified residue (phosphoserine); the 'n-terminal globular head' region

Full VCL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: dilated cardiomyopathy 1W

Similar variants

VCL p.Ser600= Likely benign ★★ 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-ser600arg (accessed [today's date]).

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