# NM_012120.3(CD2AP):c.1654C>T (p.Pro552Ser)

https://sugi.bio/variant/cd2ap-p-pro552ser

## Summary

**CD2AP p.Pro552Ser (c.1654C>T)** is classified **Conflicting classifications of pathogenicity** in CD2AP (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-12-13). AlphaMissense: likely benign (0.0662); Very rare (popmax 0.00223%, eas); Associated with Inborn genetic diseases.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · 2 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the CD2AP gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to Inborn genetic diseases.

*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.Pro552Ser |
| Coding change (HGVS c.) | c.1654C>T |
| MANE Select transcript | [NM_012120](https://www.ncbi.nlm.nih.gov/nuccore/NM_012120) |
| Variant type | single nucleotide variant |
| Location | chr6:47609144-47609144 (GRCh38) |
| ClinVar | [VCV3593703](https://www.ncbi.nlm.nih.gov/clinvar/variation/3593703/) |

**All HGVS expressions:** `NC_000006.11:g.47576880C>T`, `NC_000006.12:g.47609144C>T`, `NG_008878.1:g.136356C>T`, `NM_012120.2:c.1654C>T`, `NM_012120.3:c.1654C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0662)
- REVEL 0.041 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.936 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 0.023, GERP -0.78, phastCons 0.789 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 15.43**. 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.*
- Regional missense constraint: **o/e 1.05** across the covering region of the MANE Select transcript (47,478,245–47,624,224), spanning 145,979 bp. Chi-square p 0.14. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.83 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00223%** (eas) · 1/44,806 in the highest group · 1/1,613,098 alleles overall — very rare (popmax 0.00223%, eas).

*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}


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.


### 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-12-13.

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

**Submission history:** 2 submissions (2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-06-20 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-12-13 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related CD2AP variant pages (same residue, condition, or type): [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), [CD2AP c.*496A>G](/variant/cd2ap-c-star-496a-g).

### 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 3593703). 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.*