Is VCL p.Thr697= (c.2091C>A) pathogenic?

VCL p.Thr697= (c.2091C>A) is classified Likely benign in VCL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-02). Very rare (popmax 0.005%, amr); Associated with Cardiovascular phenotype.

What condition is associated with VCL p.Thr697= (c.2091C>A)?

VCL p.Thr697= (c.2091C>A) is associated with Cardiovascular phenotype, dilated cardiomyopathy 1W (ClinVar).

How common is VCL p.Thr697= (c.2091C>A) in the general population?

VCL p.Thr697= (c.2091C>A) is very rare (popmax 0.005%, amr) (gnomAD).

VCL p.Thr697=

c.2091C>A · rs775493699 · VCV260312

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.14	GERP -2.5, phastCons 0.95
Overall
CADD	6.867	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/60,014 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000186% 3/1,614,102 alleles · very rare exomes 3/1,461,834 · genomes 0/152,268 · 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.Thr697=
Coding: c.2091C>A
MANE Select: NM_014000
dbSNP: rs775493699
Type: single nucleotide variant
Location: chr10:74103888 (GRCh38)
Gene constraint: LOEUF 0.461 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.69 · 37 PDB
Residue 697: 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

Also linked: dilated cardiomyopathy 1W

Similar variants

VCL p.Thr697_Gln701del 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-thr697 (accessed [today's date]).

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