Is VCL p.Ser260= (c.780C>T) pathogenic?

VCL p.Ser260= (c.780C>T) is classified Likely benign in VCL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-01). Ultra-rare (popmax 0.066%, mid); Associated with Cardiovascular phenotype.

What condition is associated with VCL p.Ser260= (c.780C>T)?

VCL p.Ser260= (c.780C>T) is associated with Cardiovascular phenotype, dilated cardiomyopathy 1W (ClinVar).

How common is VCL p.Ser260= (c.780C>T) in the general population?

VCL p.Ser260= (c.780C>T) is ultra-rare (popmax 0.066%, mid) (gnomAD).

VCL p.Ser260=

c.780C>T · rs774377548 · VCV387383

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.066%, mid)

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 1.1	GERP 1.2, phastCons 1
Overall
CADD	12.52	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.066% Middle Eastern · 4/6,060 alleles

Filtering AF 0.0225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.00062% 10/1,614,116 alleles · ultra-rare exomes 10/1,461,828 · genomes 0/152,288 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.066%	1,515
Remaining individualsnot grpmax-eligible	0.008%	12,502
European (non-Finnish)	8.47e-05%	1,180,011

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.Ser260=
Coding: c.780C>T
MANE Select: NM_014000
dbSNP: rs774377548
Type: single nucleotide variant
Location: chr10:74074900 (GRCh38)
Gene constraint: LOEUF 0.461 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.69 · 37 PDB
Residue 260: a modified residue (phosphoserine); 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 p.Ser260Arg 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-ser260 (accessed [today's date]).

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