Is VCL p.Pro943fs (c.2828_2829del) pathogenic?

VCL p.Pro943fs (c.28282829del) is classified Conflicting classifications of pathogenicity in VCL (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-27). Ultra-rare (popmax 0.0373%, afr); Associated with Cardiovascular phenotype.

What condition is associated with VCL p.Pro943fs (c.2828_2829del)?

VCL p.Pro943fs (c.2828_2829del) is associated with Cardiovascular phenotype, dilated cardiomyopathy, dilated cardiomyopathy 1W (ClinVar).

How common is VCL p.Pro943fs (c.2828_2829del) in the general population?

VCL p.Pro943fs (c.2828_2829del) is ultra-rare (popmax 0.0373%, afr) (gnomAD).

VCL p.Pro943fs

c.2828_2829del · rs781036800 · VCV202163

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0373%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 19 of 22
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.4	GERP -2.2, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0373% African / African-American · 28/75,038 alleles

Filtering AF 0.0265% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0229%

Overall 0.00273% 44/1,614,194 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0373%	2,680
Admixed American	0.00833%	12,004
Remaining individualsnot grpmax-eligible	0.0032%	31,254
South Asian	0.0022%	45,543
European (non-Finnish)	0.000593%	168,576

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.Pro943fs
Coding: c.2828_2829del
MANE Select: NM_014000
dbSNP: rs781036800
Type: Deletion
Location: chr10:74111991 (GRCh38)
Gene constraint: LOEUF 0.461 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.69 · 37 PDB
Residue 943: the 'c-terminal tail' region; a UniProt-annotated variant site (in)

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 dilated cardiomyopathy 1W hypertrophic cardiomyopathy 15

Similar variants

VCL p.Pro943Ala Likely benign ★★ same residue
VCL p.Pro943_Asp944insTer Uncertain significance ★ same residue
VCL p.Pro943His Uncertain significance ★ ⚠ same residue
VCL p.Pro943Leu Uncertain significance ★ ⚠ same residue
VCL p.Pro943Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
VCL c.168+1del Uncertain significance ★★ same condition
VCL p.Asp944fs Uncertain significance ★★ same condition
VCL p.Gln334_Leu338del 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-pro943fs (accessed [today's date]).

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