# NM_033337.3(CAV3):c.123T>C (p.Phe41=)

https://sugi.bio/variant/cav3-p-phe41

## Summary

**CAV3 p.Phe41= (c.123T>C)** is classified **Benign/Likely benign** in CAV3 (ClinVar, Multiple submitters, 17 submitters; last evaluated 2026-02-04). Common (popmax 29%, afr) — too common for a highly-penetrant pathogenic allele; Associated with Cardiovascular phenotype.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs13087941 · 17 submitters · 4 linked conditions · common (popmax 29%, afr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the CAV3 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 17 submitters, and is linked to Cardiovascular phenotype.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CAV3](https://sugi.bio/atlas/gene/CAV3/) |
| Protein change (HGVS p.) | p.Phe41= |
| Coding change (HGVS c.) | c.123T>C |
| MANE Select transcript | [NM_033337](https://www.ncbi.nlm.nih.gov/nuccore/NM_033337) |
| dbSNP | [rs13087941](https://www.ncbi.nlm.nih.gov/snp/rs13087941/) |
| Variant type | single nucleotide variant |
| Location | chr3:8745534-8745534 (GRCh38) |
| ClinVar | [VCV31717](https://www.ncbi.nlm.nih.gov/clinvar/variation/31717/) |

**All HGVS expressions:** `LRG_329:g.16725T>C`, `LRG_329t1:c.123T>C`, `NC_000003.11:g.8787220T>C`, `NC_000003.12:g.8745534T>C`, `NG_008797.2:g.16725T>C`, `NM_001234.5:c.123T>C`, `NM_033337.3:c.123T>C`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 29%, afr) — too common for a highly-penetrant pathogenic allele.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -7.478, GERP -5.35 — fast-evolving / accelerated position
- CADD: **PHRED 0.212**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **29%** (afr) · FAF95 28.6% · FAF99 28.5% · 21,696/74,932 in the highest group · 358,479/1,612,768 alleles overall — common (popmax 29%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 29% | 3 |
| Finnish (not grpmax-eligible) | 26.3% | 4 |
| European (non-Finnish) | 24.4% | 4 |
| Remaining individuals (not grpmax-eligible) | 20.2% | 5 |
| Amish (not grpmax-eligible) | 17% | 6 |
| Ashkenazi Jewish (not grpmax-eligible) | 15.4% | 7 |
| Admixed American | 12.1% | 8 |
| Middle Eastern | 10.3% | 10 |
| South Asian | 6.92% | 14 |
| East Asian | 0.428% | 234 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CAV3** population constraint: LOEUF 1.064, pLI 0.039666, missense-Z 0.99211. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **long QT syndrome** — Limited (AD)
- **caveolinopathy** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 88.54, 55% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of CAV3 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** CAV3's established molecular role includes calcium channel regulator activity.


### Pathways affected {#pathways}

CAV3 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Smooth Muscle Contraction](https://reactome.org/content/detail/R-HSA-445355) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** calcium channel regulator activity, sodium channel regulator activity, transmembrane transporter binding, protein-containing complex binding, molecular adaptor activity, connexin binding.

**Biological process:** regulation of heart rate, regulation of heart contraction, negative regulation of cardiac muscle hypertrophy, regulation of skeletal muscle contraction, regulation of signal transduction by receptor internalization, regulation of membrane potential.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** conflicting (13 Benign, 3 Likely benign, 1 not provided).

**Submission history:** 17 submissions (2011–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Likely benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics, Academic Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Benign | no assertion criteria provided | clinical testing |  |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Benign | criteria provided, single submitter | clinical testing | 2024-12-19 |
| Eurofins Ntd Llc (ga) | Benign | criteria provided, single submitter | clinical testing | 2013-07-29 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2011-07-09 |
| Athena Diagnostics | Benign | criteria provided, single submitter | clinical testing | 2017-04-29 |
| Leiden Muscular Dystrophy (CAV3) | not provided | no classification provided | curation | 2012-04-15 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2017-07-24 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-26 |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Benign | criteria provided, single submitter | clinical testing | 2012-01-25 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Benign | no assertion criteria provided | clinical testing |  |
| Ambry Genetics | Benign | criteria provided, single submitter | clinical testing | 2015-03-09 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/), [long QT syndrome](https://sugi.bio/atlas/disease/long-qt-syndrome/), [caveolinopathy](https://sugi.bio/atlas/disease/caveolinopathy/), [rippling muscle disease 2](https://sugi.bio/atlas/disease/rippling-muscle-disease-2/).

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, not provided, not specified, Long QT syndrome, Caveolinopathy, Rippling muscle disease 2, AllHighlyPenetrant, none provided, CAV3-Related Rippling Muscle Disease, Limb-girdle muscular dystrophy, type 1C.

## Similar variants {#similar}

Related CAV3 variant pages (same residue, condition, or type): [CAV3 c.114+2T>C](/variant/cav3-c-114-plus-2t-c), [CAV3 p.Ala46Thr](/variant/cav3-p-ala46thr), [CAV3 p.Arg27Gln](/variant/cav3-p-arg27gln), [CAV3 p.Trp71Ter](/variant/cav3-p-trp71ter), [CAV3 c.114+5G>C](/variant/cav3-c-114-plus-5g-c), [CAV3 c.*134G>A](/variant/cav3-c-star-134g-a), [CAV3 c.*592G>A](/variant/cav3-c-star-592g-a), [CAV3 c.*658T>A](/variant/cav3-c-star-658t-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 31717). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*