# NM_012232.6(CAVIN1):c.232C>A (p.Arg78=)

https://sugi.bio/variant/cavin1-p-arg78

## Summary

**CAVIN1 p.Arg78= (c.232C>A)** is classified **Conflicting classifications of pathogenicity** in CAVIN1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-19). Ultra-rare (popmax 0.014%, nfe); Associated with congenital generalized lipodystrophy type 4.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs750373957 · 3 submitters · 1 linked condition · ultra-rare (popmax 0.014%, nfe)

## For patients & families {#patients}

This is a change in the CAVIN1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to congenital generalized lipodystrophy type 4.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010937/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CAVIN1](https://sugi.bio/atlas/gene/CAVIN1/) |
| Protein change (HGVS p.) | p.Arg78= |
| Coding change (HGVS c.) | c.232C>A |
| MANE Select transcript | [NM_012232](https://www.ncbi.nlm.nih.gov/nuccore/NM_012232) |
| dbSNP | [rs750373957](https://www.ncbi.nlm.nih.gov/snp/rs750373957/) |
| Variant type | single nucleotide variant |
| Location | chr17:42422866-42422866 (GRCh38) |
| ClinVar | [VCV889148](https://www.ncbi.nlm.nih.gov/clinvar/variation/889148/) |

**All HGVS expressions:** `NC_000017.10:g.40574884G>T`, `NC_000017.11:g.42422866G>T`, `NG_015845.2:g.5455C>A`, `NM_012232.6:c.232C>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 5.501, GERP -0.488, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 14.92**. 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** — this absence is genuinely unknown. Where a position sits between the lowest and the highest record the release holds for its gene, an absent score is a result and we state it as one; this position falls outside them, or the gene has no scored position at all, so that test did not reach here. It may lie outside the scored MANE transcript scope, or it may have been scored with all four deltas below Δ0.2 just past the last surviving record. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.014%** (nfe) · FAF95 0.0122% · FAF99 0.0116% · 165/1,180,018 in the highest group · 169/1,613,946 alleles overall — ultra-rare (popmax 0.014%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.014% | 7,152 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,827 |
| African / African-American | 0.00133% | 74,932 |

*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}

**CAVIN1** population constraint: LOEUF 1.092, pLI 9.0236e-05, missense-Z 0.58859. *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):

- **lipodystrophy** — Definitive (AR)

## Protein context {#protein}

Residue **78** lies in the 'required for homotrimerization and for interaction with cavin2 and cavin3' region; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 68.03, 24% of residues very-high.

**3 experimental structure(s)** (PDB): [9EG6](https://www.rcsb.org/structure/9EG6), [9EGN](https://www.rcsb.org/structure/9EGN), [9EIU](https://www.rcsb.org/structure/9EIU) — incl. mutant structure 9EG6.

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

*Describes the biological roles of CAVIN1 (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:** CAVIN1's established molecular role includes RNA binding. p.Arg78= falls in the required for homotrimerization and for interaction with cavin2 and cavin3 region.


### Pathways affected {#pathways}

CAVIN1 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [RHOA GTPase cycle](https://reactome.org/content/detail/R-HSA-8980692) | other |
| [RHOB GTPase cycle](https://reactome.org/content/detail/R-HSA-9013026) | other |
| [RHOC GTPase cycle](https://reactome.org/content/detail/R-HSA-9013106) | other |
| [RNA Polymerase I Transcription Termination](https://reactome.org/content/detail/R-HSA-73863) | other |

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

**Molecular function:** RNA binding, rRNA primary transcript binding, identical protein binding.

**Biological process:** transcription initiation at RNA polymerase I promoter, termination of RNA polymerase I transcription.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-12-19.

**Submitter consensus:** conflicting (2 Likely benign, 1 Uncertain significance).

**Submission history:** 3 submissions (2018–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-12 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-09-17 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-19 |

## Associated conditions {#conditions}

[congenital generalized lipodystrophy type 4](https://sugi.bio/atlas/disease/congenital-generalized-lipodystrophy-type-4/).

**Reported phenotype names (ClinVar):** Congenital generalized lipodystrophy type 4, CAVIN1-related disorder, not provided, CAVIN1-related condition, BERARDINELLI-SEIP CONGENITAL LIPODYSTROPHY, TYPE 4, WITH MUSCULAR DYSTROPHY, none provided.

## Similar variants {#similar}

Related CAVIN1 variant pages (same residue, condition, or type): [CAVIN1 c.*1110C>T](/variant/cavin1-c-star-1110c-t), [CAVIN1 c.*195C>G](/variant/cavin1-c-star-195c-g), [CAVIN1 p.Ala21Val](/variant/cavin1-p-ala21val), [CAVIN1 p.Arg227Trp](/variant/cavin1-p-arg227trp), [CAVIN1 p.Leu172Val](/variant/cavin1-p-leu172val), [CAVIN1 p.Pro283Ser](/variant/cavin1-p-pro283ser), [CAVIN1 p.Thr279Arg](/variant/cavin1-p-thr279arg), [CAVIN1 p.Val306Ala](/variant/cavin1-p-val306ala).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2026-10-14); 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 889148). 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.*