Is VCL p.Pro951Ser (c.2851C>T) pathogenic?

VCL p.Pro951Ser (c.2851C>T) is classified Uncertain significance in VCL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-18). AlphaMissense: ambiguous (0.4582); Very rare (popmax 0.00833%, amr); Associated with dilated cardiomyopathy 1W.

What condition is associated with VCL p.Pro951Ser (c.2851C>T)?

VCL p.Pro951Ser (c.2851C>T) is associated with dilated cardiomyopathy 1W (ClinVar).

How common is VCL p.Pro951Ser (c.2851C>T) in the general population?

VCL p.Pro951Ser (c.2851C>T) is very rare (popmax 0.00833%, amr) (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.Pro951Ser (c.2851C>T)?

AlphaMissense predicts ambiguous (score 0.4582) — an in-silico prediction, not a clinical call.

VCL p.Pro951Ser

c.2851C>T · rs774356864 · VCV1421480

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4582 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

dilated cardiomyopathy 1W

Computational evidence

Protein change
AlphaMissense	0.4582	ambiguous
REVEL	0.261	benign-leaning
SaProt	LLR -6.60	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 2,946 bp · p 0.6 · regional, not allelic
Overall
CADD	25.1	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

Grpmax group 0.00833% Admixed American · 5/60,016 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00206%

Overall 0.000372% 6/1,614,102 alleles · very rare exomes 5/1,461,894 · genomes 1/152,208 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,003
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Pro951Ser
Coding: c.2851C>T
MANE Select: NM_014000
dbSNP: rs774356864
Type: single nucleotide variant
Location: chr10:74112014 (GRCh38)
Gene constraint: LOEUF 0.461 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.69 · 37 PDB
Residue 951: the 'c-terminal tail' region

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

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 p.Pro951Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
VCL p.Pro951Thr Uncertain significance ★ ⚠ same residue
VCL p.Pro951Leu 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

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-pro951ser (accessed [today's date]).

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