Is CAV3 p.Phe133= (c.399C>T) pathogenic?

CAV3 p.Phe133= (c.399C>T) is classified Conflicting classifications of pathogenicity in CAV3 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-07). Ultra-rare (popmax 0.0657%, mid); Associated with Cardiovascular phenotype.

What condition is associated with CAV3 p.Phe133= (c.399C>T)?

CAV3 p.Phe133= (c.399C>T) is associated with Cardiovascular phenotype, long QT syndrome (ClinVar).

How common is CAV3 p.Phe133= (c.399C>T) in the general population?

CAV3 p.Phe133= (c.399C>T) is ultra-rare (popmax 0.0657%, mid) (gnomAD).

CAV3 p.Phe133=

c.399C>T · rs769859957 · VCV281822

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0657%, mid)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.4	GERP -5.9
Overall
CADD	5.64	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0657% Middle Eastern · 4/6,084 alleles

Filtering AF 0.0224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.00514% 83/1,613,764 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0657%	1,521
South Asian	0.022%	4,554
Admixed American	0.00833%	12,002
Remaining individualsnot grpmax-eligible	0.0064%	15,622
African / African-American	0.004%	24,981
European (non-Finnish)	0.00398%	25,107

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: CAV3
Protein: p.Phe133=
Coding: c.399C>T
MANE Select: NM_033337
dbSNP: rs769859957
Type: single nucleotide variant
Location: chr3:8745810 (GRCh38)
Gene constraint: LOEUF 1.064 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 88.54

Full CAV3 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: long QT syndrome

Similar variants

CAV3 c.114+2T>C Pathogenic ★★ same condition
CAV3 p.Ala46Thr Pathogenic/Likely pathogenic ★★ same condition
CAV3 p.Arg27Gln Pathogenic ★★ same condition
CAV3 p.Trp71Ter Pathogenic/Likely pathogenic ★★ same condition
CAV3 c.114+5G>C Uncertain significance ★★ same condition
CAV3 p.Ala102Val Uncertain significance ★★ ⚠ same condition
CAV3 p.Ala134Glu Uncertain significance ★★ ⚠ same condition
CAV3 p.Ala134Pro 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/cav3-p-phe133 (accessed [today's date]).

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