# NM_012120.3(CD2AP):c.330_334del (p.Arg111fs)

https://sugi.bio/variant/cd2ap-p-arg111fs

## Summary

**CD2AP p.Arg111fs (c.330_334del)** is classified **Likely pathogenic** in CD2AP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-07). Associated with focal segmental glomerulosclerosis 3, susceptibility to.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the CD2AP gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to focal segmental glomerulosclerosis 3, susceptibility to.

*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 | [CD2AP](https://sugi.bio/atlas/gene/CD2AP/) |
| Protein change (HGVS p.) | p.Arg111fs |
| Coding change (HGVS c.) | c.330_334del |
| MANE Select transcript | [NM_012120](https://www.ncbi.nlm.nih.gov/nuccore/NM_012120) |
| Variant type | Deletion |
| Location | chr6:47544616-47544620 (GRCh38) |
| ClinVar | [VCV4292755](https://www.ncbi.nlm.nih.gov/clinvar/variation/4292755/) |

**All HGVS expressions:** `NC_000006.11:g.47512352_47512356del`, `NC_000006.12:g.47544616_47544620del`, `NG_008878.1:g.71828_71832del`, `NM_012120.3:c.330_334del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 4.519, GERP -0.269, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.815, pLI 9.8434e-06. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 4 of 18**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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}

**CD2AP** population constraint: LOEUF 0.815, pLI 9.8434e-06, missense-Z -0.16853. *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):

- **inherited focal segmental glomerulosclerosis** — Moderate (AD)
- **focal segmental glomerulosclerosis 3, susceptibility to** — Definitive (AR)

## Protein context {#protein}

Residue **111** lies in the sh3 2 domain; the 'interaction with anln and localization to the midbody' region.

AlphaFold model confidence (whole protein): pLDDT 63.04, 31% of residues very-high.

**12 experimental structure(s)** (PDB): [2FEI](https://www.rcsb.org/structure/2FEI), [2J6F](https://www.rcsb.org/structure/2J6F), [2J6K](https://www.rcsb.org/structure/2J6K), [2J6O](https://www.rcsb.org/structure/2J6O), [2J7I](https://www.rcsb.org/structure/2J7I), [3AA6](https://www.rcsb.org/structure/3AA6).

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

*Describes the biological roles of CD2AP (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:** CD2AP's established molecular role includes SH3 domain binding. p.Arg111fs falls in the sh3 2 domain.


### Pathways affected {#pathways}

CD2AP participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Nephrin family interactions](https://reactome.org/content/detail/R-HSA-373753) | electronic |

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

**Molecular function:** SH3 domain binding, cadherin binding.

**Biological process:** actin filament organization, positive regulation of protein secretion, negative regulation of small GTPase mediated signal transduction.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-10-07.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| 3billion | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-10-07 |

## Associated conditions {#conditions}

[focal segmental glomerulosclerosis 3, susceptibility to](https://sugi.bio/atlas/disease/focal-segmental-glomerulosclerosis-3-susceptibility-to/).

**Reported phenotype names (ClinVar):** Focal segmental glomerulosclerosis 3, susceptibility to.

## Similar variants {#similar}

Related CD2AP variant pages (same residue, condition, or type): [CD2AP p.Arg111His](/variant/cd2ap-p-arg111his), [CD2AP p.Gln255fs](/variant/cd2ap-p-gln255fs), [CD2AP c.1879-3del](/variant/cd2ap-c-1879-minus-3del), [CD2AP p.Arg111Cys](/variant/cd2ap-p-arg111cys), [CD2AP p.Asn581fs](/variant/cd2ap-p-asn581fs), [CD2AP p.Ser256fs](/variant/cd2ap-p-ser256fs), [CD2AP c.1274+3A>G](/variant/cd2ap-c-1274-plus-3a-g), [CD2AP c.1633-6T>A](/variant/cd2ap-c-1633-minus-6t-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 4292755). 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.*