Is VCL p.Pro951Arg (c.2852C>G) pathogenic?

VCL p.Pro951Arg (c.2852C>G) is classified Conflicting classifications of pathogenicity in VCL (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-24). AlphaMissense: likely pathogenic (0.6071); Ultra-rare (popmax 0.0164%, mid); Associated with Cardiovascular phenotype.

What condition is associated with VCL p.Pro951Arg (c.2852C>G)?

VCL p.Pro951Arg (c.2852C>G) is associated with Cardiovascular phenotype, dilated cardiomyopathy 1W (ClinVar).

How common is VCL p.Pro951Arg (c.2852C>G) in the general population?

VCL p.Pro951Arg (c.2852C>G) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about VCL p.Pro951Arg (c.2852C>G)?

AlphaMissense predicts likely pathogenic (score 0.6071) — an in-silico prediction, not a clinical call.

VCL p.Pro951Arg

c.2852C>G · rs368570586 · VCV45601

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.6071 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.6071	likely pathogenic
REVEL	0.329	indeterminate
SaProt	LLR -7.53	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 2,946 bp · p 0.6 · regional, not allelic
Overall
CADD	24.0	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00204% 33/1,614,084 alleles · ultra-rare exomes 31/1,461,894 · genomes 2/152,190 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0372%	2,692
Middle Easterngrpmax	0.0164%	6,084
European (non-Finnish)	0.00161%	62,108
Remaining individualsnot grpmax-eligible	0.0016%	62,490
South Asian	0.0011%	91,090

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro951Arg
Coding: c.2852C>G
MANE Select: NM_014000
dbSNP: rs368570586
Type: single nucleotide variant
Location: chr10:74112015 (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

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dilated cardiomyopathy 1W

Similar variants

VCL p.Pro951Ser Uncertain significance ★★ ⚠ same residue
VCL p.Pro951Leu Uncertain significance ★ same residue
VCL p.Pro951Thr 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-pro951arg (accessed [today's date]).

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