Is CAV3 p.Ala46Val (c.137C>T) pathogenic?

CAV3 p.Ala46Val (c.137C>T) is classified Likely pathogenic in CAV3 (ClinVar, Single submitter, 3 submitters; last evaluated 2016-01-25). AlphaMissense: likely pathogenic (0.9819); Absent from gnomAD v4.1; Associated with rippling muscle disease 2.

What condition is associated with CAV3 p.Ala46Val (c.137C>T)?

CAV3 p.Ala46Val (c.137C>T) is associated with rippling muscle disease 2 (ClinVar).

How common is CAV3 p.Ala46Val (c.137C>T) in the general population?

CAV3 p.Ala46Val (c.137C>T) is absent from gnomAD v4.1 (gnomAD).

How is Rippling muscle disease inherited?

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

What do computational predictors say about CAV3 p.Ala46Val (c.137C>T)?

AlphaMissense predicts likely pathogenic (score 0.9819) — an in-silico prediction, not a clinical call.

CAV3 p.Ala46Val

c.137C>T · rs116840773 · VCV8282

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9819 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

rippling muscle disease 2

Computational evidence

Protein change
AlphaMissense	0.9819	likely pathogenic ✓ concordant with ClinVar · top 8% in CAV3
REVEL	0.902	moderately pathogenic-leaning
SaProt	LLR -7.21	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.7, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 12 kb · p 0.021 · 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

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: CAV3
Protein: p.Ala46Val
Coding: c.137C>T
MANE Select: NM_033337
dbSNP: rs116840773
Type: single nucleotide variant
Location: chr3:8745548 (GRCh38)
Gene constraint: LOEUF 1.064 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 88.54
Residue 46: a UniProt-annotated variant site (in rmd2; decreased surface expression of the cav3 protein); a UniProt-annotated variant site (in rmd2)

Full CAV3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

rippling muscle disease 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Rippling muscle disease (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Adolescent, Adult, Childhood, Elderly, Infancy

Similar variants

CAV3 p.Ala46Thr Pathogenic/Likely pathogenic ★★ ⚠ same residue
CAV3 p.Ala46= Likely benign ★ same residue
CAV3 c.114+2T>C Pathogenic ★★ same condition
CAV3 p.Arg27Gln Pathogenic ★★ same condition
CAV3 c.*134G>A Uncertain significance ★★ same condition
CAV3 c.*592G>A Uncertain significance ★★ same condition
CAV3 c.*658T>A Uncertain significance ★★ same condition
CAV3 c.*741G>A 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-ala46val (accessed [today's date]).

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