Is VCL p.Ala1111Val (c.3332C>T) pathogenic?

VCL p.Ala1111Val (c.3332C>T) is classified Uncertain significance in VCL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-30). AlphaMissense: likely pathogenic (0.9444); Absent from gnomAD v4.1; Associated with Cardiovascular phenotype.

What condition is associated with VCL p.Ala1111Val (c.3332C>T)?

VCL p.Ala1111Val (c.3332C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is VCL p.Ala1111Val (c.3332C>T) in the general population?

VCL p.Ala1111Val (c.3332C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about VCL p.Ala1111Val (c.3332C>T)?

AlphaMissense predicts likely pathogenic (score 0.9444) — an in-silico prediction, not a clinical call.

VCL p.Ala1111Val

c.3332C>T · VCV3979534

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9444 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9444	likely pathogenic
REVEL	0.218	benign-leaning
SaProt	LLR -7.68	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.5, phastCons 1
Regional constraint	o/e 0.45	unconstrained · MANE · 6,073 bp · p 2.6e-15 · regional, not allelic
Overall
CADD	28.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: VCL
Protein: p.Ala1111Val
Coding: c.3332C>T
MANE Select: NM_014000
Type: single nucleotide variant
Location: chr10:74118096 (GRCh38)
Gene constraint: LOEUF 0.461 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.69 · 37 PDB
Residue 1111: the 'c-terminal tail' 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.Ala1111= Benign/Likely benign ★★ same residue
VCL p.Ala1111Ser Uncertain significance ★ same residue
VCL p.Ala1111Phe Uncertain significance ★ same residue
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

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-ala1111val (accessed [today's date]).

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