# NM_012120.3(CD2AP):c.250C>T (p.Arg84Ter)

https://sugi.bio/variant/cd2ap-p-arg84ter

## Summary

**CD2AP p.Arg84Ter (c.250C>T)** is classified **Likely pathogenic** in CD2AP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-17). Very rare (popmax 0.00439%, sas); Associated with focal segmental glomerulosclerosis 3, susceptibility to.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs368795308 · 1 submitter · 1 linked condition · very rare (popmax 0.00439%, sas)

## 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.Arg84Ter |
| Coding change (HGVS c.) | c.250C>T |
| MANE Select transcript | [NM_012120](https://www.ncbi.nlm.nih.gov/nuccore/NM_012120) |
| dbSNP | [rs368795308](https://www.ncbi.nlm.nih.gov/snp/rs368795308/) |
| Variant type | single nucleotide variant |
| Location | chr6:47533686-47533686 (GRCh38) |
| ClinVar | [VCV1179189](https://www.ncbi.nlm.nih.gov/clinvar/variation/1179189/) |

**All HGVS expressions:** `NC_000006.11:g.47501422C>T`, `NC_000006.12:g.47533686C>T`, `NG_008878.1:g.60898C>T`, `NM_012120.3:c.250C>T`

## 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 3.257, GERP 2.08, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — 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 3 of 18**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 40.0**. 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 **0.00439%** (sas) · FAF95 0.00143% · FAF99 0.000891% · 4/91,090 in the highest group · 13/1,613,960 alleles overall — very rare (popmax 0.00439%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00439% | 22,773 |
| African / African-American | 0.00133% | 74,922 |
| European (non-Finnish) | 0.000678% | 147,498 |

*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 **84** lies in 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.Arg84Ter falls in the interaction with anln and localization to the midbody region.


### 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 2024-05-17.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-05-17 |

## 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.Arg84Gln](/variant/cd2ap-p-arg84gln), [CD2AP c.1274+3A>G](/variant/cd2ap-c-1274-plus-3a-g), [CD2AP c.1633-6T>A](/variant/cd2ap-c-1633-minus-6t-a), [CD2AP c.-130C>G](/variant/cd2ap-c-minus-130c-g), [CD2AP c.-166A>G](/variant/cd2ap-c-minus-166a-g), [CD2AP c.*319A>C](/variant/cd2ap-c-star-319a-c), [CD2AP c.*452C>G](/variant/cd2ap-c-star-452c-g), [CD2AP c.*494G>A](/variant/cd2ap-c-star-494g-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 2026-10-14); 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 1179189). 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.*