Is VCL p.Ser439= (c.1317T>C) pathogenic?

VCL p.Ser439= (c.1317T>C) is classified Conflicting classifications of pathogenicity in VCL (ClinVar, Conflicting submitters, 17 submitters; last evaluated 2026-03-01). Rare (popmax 0.677%, mid); Associated with Cardiovascular phenotype.

What condition is associated with VCL p.Ser439= (c.1317T>C)?

VCL p.Ser439= (c.1317T>C) is associated with Cardiovascular phenotype, cardiomyopathy, dilated cardiomyopathy 1W (ClinVar).

How common is VCL p.Ser439= (c.1317T>C) in the general population?

VCL p.Ser439= (c.1317T>C) is rare (popmax 0.677%, mid) (gnomAD).

VCL p.Ser439=

c.1317T>C · rs71579355 · VCV45577

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 17 submitters

gnomAD v4.1

Rare

rare (popmax 0.677%, 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 0.35	GERP -1.4, phastCons 1
Overall
CADD	8.421	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.677% Middle Eastern · 41/6,060 alleles

Filtering AF 0.622% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.618%

Overall 0.536% 8,653/1,614,224 alleles · rare exomes 7,998/1,461,876 · genomes 655/152,348 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.677%	148
European (non-Finnish)	0.634%	158
Admixed American	0.618%	162
Ashkenazi Jewishnot grpmax-eligible	0.483%	207
Remaining individualsnot grpmax-eligible	0.467%	214
Amishnot grpmax-eligible	0.219%	456
South Asian	0.211%	474
African / African-American	0.117%	853
Finnishnot grpmax-eligible	0.0578%	1,731

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.Ser439=
Coding: c.1317T>C
MANE Select: NM_014000
dbSNP: rs71579355
Type: single nucleotide variant
Location: chr10:74090163 (GRCh38)
Gene constraint: LOEUF 0.461 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.69 · 37 PDB
Residue 439: 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: cardiomyopathy dilated cardiomyopathy 1W

Similar variants

VCL p.Ser439Pro 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-ser439 (accessed [today's date]).

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