Is VCL p.Lys738= (c.2214G>A) pathogenic?

VCL p.Lys738= (c.2214G>A) is classified Likely benign in VCL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-28). Very rare (popmax 8.47e-05%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with VCL p.Lys738= (c.2214G>A)?

VCL p.Lys738= (c.2214G>A) is associated with Cardiovascular phenotype (ClinVar).

How common is VCL p.Lys738= (c.2214G>A) in the general population?

VCL p.Lys738= (c.2214G>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

VCL p.Lys738=

c.2214G>A · VCV3467787

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.22	donor loss at this position · masked 0 · deltas
Constraint at this position
Conservation	phyloP 7.3	GERP 1.9, phastCons 1
Overall
CADD	8.818	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,030 alleles

Overall 6.84e-05% 1/1,461,892 alleles · very rare

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.Lys738=
Coding: c.2214G>A
MANE Select: NM_014000
Type: single nucleotide variant
Location: chr10:74105133 (GRCh38)
Gene constraint: LOEUF 0.461 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.69 · 37 PDB
Residue 738: 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 c.1352+5G>A Uncertain significance ★★ same condition
VCL c.1543+4A>G Uncertain significance ★★ same condition
VCL c.2132-3C>A Uncertain significance ★★ same condition
VCL c.239+3G>A Uncertain significance ★★ same condition
VCL p.Ala1023Thr Uncertain significance ★★ ⚠ same condition
VCL p.Ala1120Thr Uncertain significance ★★ ⚠ same condition
VCL p.Ala257Thr Uncertain significance ★★ ⚠ same condition
VCL p.Ala340Val 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-lys738 (accessed [today's date]).

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