Is CAV3 p.Cys72Trp (c.216C>G) pathogenic?

CAV3 p.Cys72Trp (c.216C>G) is classified Conflicting classifications of pathogenicity in CAV3 (ClinVar, Conflicting submitters, 21 submitters; last evaluated 2026-04-01). AlphaMissense: likely pathogenic (0.9037); Rare (popmax 0.25%, nfe); Associated with limb-girdle muscular dystrophy.

What condition is associated with CAV3 p.Cys72Trp (c.216C>G)?

CAV3 p.Cys72Trp (c.216C>G) is associated with limb-girdle muscular dystrophy, long QT syndrome, cardiomyopathy (ClinVar).

How common is CAV3 p.Cys72Trp (c.216C>G) in the general population?

CAV3 p.Cys72Trp (c.216C>G) is rare (popmax 0.25%, nfe) (gnomAD).

What do computational predictors say about CAV3 p.Cys72Trp (c.216C>G)?

AlphaMissense predicts likely pathogenic (score 0.9037) — an in-silico prediction, not a clinical call.

CAV3 p.Cys72Trp

c.216C>G · rs116840776 · VCV8279

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 21 submitters

AlphaMissense

likely pathogenic

0.9037 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.25%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

limb-girdle muscular dystrophy

Computational evidence

Protein change
AlphaMissense	0.9037	likely pathogenic
REVEL	0.773	moderately pathogenic-leaning
SaProt	LLR -13.09	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -3.8, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 12 kb · p 0.021 · regional, not allelic
Overall
CADD	24.7	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 0.25% European (non-Finnish) · 2,949/1,179,996 alleles

Filtering AF 0.242% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.239%

Overall 0.217% 3,508/1,614,132 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.25%	400
South Asian	0.243%	412
Admixed American	0.237%	423
Remaining individualsnot grpmax-eligible	0.235%	425
Middle Eastern	0.0495%	2,021
African / African-American	0.0426%	2,345
Finnishnot grpmax-eligible	0.0203%	4,926
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604

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.Cys72Trp
Coding: c.216C>G
MANE Select: NM_033337
dbSNP: rs116840776
Type: single nucleotide variant
Location: chr3:8745627 (GRCh38)
Gene constraint: LOEUF 1.064 · pLI 0.04 (gnomAD)
Structure: AlphaFold pLDDT 88.54
Residue 72: a UniProt-annotated variant site (in); the 'required for interaction with dag1' region

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

Disease context

limb-girdle muscular dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: long QT syndrome cardiomyopathy hypertrophic cardiomyopathy 1 long QT syndrome 9 distal myopathy, Tateyama type caveolinopathy rippling muscle disease 2 long QT syndrome 1

Similar variants

CAV3 p.Cys72Tyr Uncertain significance ★ ⚠ same residue
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 c.*134G>A Uncertain significance ★★ same condition
CAV3 c.*592G>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-cys72trp (accessed [today's date]).

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