Is VCL p.Ala679Ser (c.2035G>T) pathogenic?

VCL p.Ala679Ser (c.2035G>T) is classified Uncertain significance in VCL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-02-18). AlphaMissense: likely benign (0.2968); Absent from gnomAD v4.1; Associated with dilated cardiomyopathy 1W.

What condition is associated with VCL p.Ala679Ser (c.2035G>T)?

VCL p.Ala679Ser (c.2035G>T) is associated with dilated cardiomyopathy 1W, dilated cardiomyopathy (ClinVar).

How common is VCL p.Ala679Ser (c.2035G>T) in the general population?

VCL p.Ala679Ser (c.2035G>T) is absent from gnomAD v4.1 (gnomAD).

How is Familial isolated dilated cardiomyopathy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about VCL p.Ala679Ser (c.2035G>T)?

AlphaMissense predicts likely benign (score 0.2968) — an in-silico prediction, not a clinical call.

VCL p.Ala679Ser

c.2035G>T · rs375392559 · VCV523618

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2968 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

dilated cardiomyopathy 1W

Computational evidence

Protein change
AlphaMissense	0.2968	likely benign
REVEL	0.331	indeterminate
SaProt	LLR -9.07	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.46	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 10	GERP 2.9, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 38 kb · p 3e-08 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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.Ala679Ser
Coding: c.2035G>T
MANE Select: NM_014000
dbSNP: rs375392559
Type: single nucleotide variant
Location: chr10:74103832 (GRCh38)
Gene constraint: LOEUF 0.461 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.69 · 37 PDB
Residue 679: 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

dilated cardiomyopathy 1W — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dilated cardiomyopathy

For Familial isolated dilated cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: All ages
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

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
VCL c.2023-1G>C 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-ala679ser (accessed [today's date]).

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