Is VCL p.Pro398Ser (c.1192C>T) pathogenic?

VCL p.Pro398Ser (c.1192C>T) is classified Conflicting classifications of pathogenicity in VCL (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-11-09). AlphaMissense: ambiguous (0.5034); Ultra-rare (popmax 0.0624%, eas); Associated with hypertrophic cardiomyopathy 15.

What condition is associated with VCL p.Pro398Ser (c.1192C>T)?

VCL p.Pro398Ser (c.1192C>T) is associated with hypertrophic cardiomyopathy 15, dilated cardiomyopathy 1W (ClinVar).

How common is VCL p.Pro398Ser (c.1192C>T) in the general population?

VCL p.Pro398Ser (c.1192C>T) is ultra-rare (popmax 0.0624%, eas) (gnomAD).

What do computational predictors say about VCL p.Pro398Ser (c.1192C>T)?

AlphaMissense predicts ambiguous (score 0.5034) — an in-silico prediction, not a clinical call.

VCL p.Pro398Ser

c.1192C>T · rs201528612 · VCV192103

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.5034 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0624%, eas)

Conditions

hypertrophic cardiomyopathy 15

Computational evidence

Protein change
AlphaMissense	0.5034	ambiguous
REVEL	0.626	indeterminate
SaProt	LLR -11.48	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.6, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 38 kb · p 3e-08 · regional, not allelic
Overall
CADD	25.5	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

Grpmax group 0.0624% East Asian · 28/44,864 alleles

Filtering AF 0.0443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0382%

Overall 0.00229% 37/1,613,990 alleles · ultra-rare exomes 30/1,461,858 · genomes 7/152,132 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0624%	1,602
Remaining individualsnot grpmax-eligible	0.0144%	6,944

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.Pro398Ser
Coding: c.1192C>T
MANE Select: NM_014000
dbSNP: rs201528612
Type: single nucleotide variant
Location: chr10:74090038 (GRCh38)
Gene constraint: LOEUF 0.461 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 86.69 · 37 PDB
Residue 398: the 'n-terminal globular head' region; the '3 x 112 aa tandem repeats' region

Full VCL gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypertrophic cardiomyopathy 15 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dilated cardiomyopathy 1W

Similar variants

VCL p.Pro398= Likely benign ★ 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
VCL c.1744-1G>T Uncertain significance ★★ same condition
VCL c.2022+5G>T 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-pro398ser (accessed [today's date]).

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