Is VCL p.Arg680fs (c.2039del) pathogenic?

VCL p.Arg680fs (c.2039del) is classified Uncertain significance in VCL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-27). Very rare (popmax 0.00333%, amr); Associated with Cardiovascular phenotype.

What condition is associated with VCL p.Arg680fs (c.2039del)?

VCL p.Arg680fs (c.2039del) is associated with Cardiovascular phenotype (ClinVar).

How common is VCL p.Arg680fs (c.2039del) in the general population?

VCL p.Arg680fs (c.2039del) is very rare (popmax 0.00333%, amr) (gnomAD).

VCL p.Arg680fs

c.2039del · VCV3467789

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

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 15 of 22
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.7	GERP 2.9, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,020 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000124% 2/1,613,986 alleles · very rare exomes 2/1,461,772 · genomes 0/152,214 · 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.Arg680fs
Coding: c.2039del
MANE Select: NM_014000
Type: Deletion
Location: chr10:74103836 (GRCh38)
Gene constraint: LOEUF 0.461 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.69 · 37 PDB
Residue 680: 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

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

Similar variants

VCL p.Arg680Cys Uncertain significance ★★ ⚠ same residue
VCL p.Arg680His Uncertain significance ★★ ⚠ same residue
VCL p.Asp944fs Uncertain significance ★★ same condition
VCL p.Gln334_Leu338del Uncertain significance ★★ same condition
VCL p.Glu200fs Uncertain significance ★★ same condition
VCL c.2023-1177_2051del Uncertain significance ★ same condition
VCL p.Ile245fs Uncertain significance ★ same condition
VCL p.Leu421fs 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-arg680fs (accessed [today's date]).

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