# NM_001353655.3(CDCP2):c.1007G>A (p.Cys336Tyr)

https://sugi.bio/variant/cdcp2-p-cys336tyr

## Summary

**CDCP2 p.Cys336Tyr (c.1007G>A)** is classified **Uncertain significance** in CDCP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-25). AlphaMissense: likely pathogenic (0.9901); Very rare (popmax 0.00223%, eas).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.00223%, eas)

## For patients & families {#patients}

This is a change in the CDCP2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [CDCP2](https://sugi.bio/atlas/gene/CDCP2/) |
| Protein change (HGVS p.) | p.Cys336Tyr |
| Coding change (HGVS c.) | c.1007G>A |
| MANE Select transcript | [NM_001353655](https://www.ncbi.nlm.nih.gov/nuccore/NM_001353655) |
| Variant type | single nucleotide variant |
| Location | chr1:54139863-54139863 (GRCh38) |
| ClinVar | [VCV3998745](https://www.ncbi.nlm.nih.gov/clinvar/variation/3998745/) |

**All HGVS expressions:** `NC_000001.10:g.54605536C>T`, `NC_000001.11:g.54139863C>T`, `NM_001353655.3:c.1007G>A`, `NM_201546.5:c.1007G>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9901)
- REVEL 0.821 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -11.782 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **donor gain** (Δ 0.30) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.591, GERP 1.97, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 5%** most-pathogenic-predicted substitutions in CDCP2 (of 2,625 modeled).
- CADD: **PHRED 28.9**. 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 0.92** across the covering region of the MANE Select transcript (54,132,971–54,152,922), spanning 19,951 bp. Chi-square p 0.072. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.30**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.30**.
- Population frequency (gnomAD v4.1): grpmax **0.00223%** (eas) · 1/44,878 in the highest group · 1/1,461,738 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}

**CDCP2** population constraint: LOEUF 1.369, pLI 1.3876e-10, missense-Z 0.96722. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **336** lies in a disulfide bond; the cub 3 domain.

AlphaFold model confidence (whole protein): pLDDT 82.43, 43% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-05-25.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-05-25 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related CDCP2 variant pages (same residue, condition, or type): [CDCP2 p.Cys336Arg](/variant/cdcp2-p-cys336arg), [CDCP2 c.1117+105C>T](/variant/cdcp2-c-1117-plus-105c-t), [CDCP2 c.1117+106C>T](/variant/cdcp2-c-1117-plus-106c-t), [CDCP2 c.1117+10G>A](/variant/cdcp2-c-1117-plus-10g-a), [CDCP2 c.1117+110G>T](/variant/cdcp2-c-1117-plus-110g-t), [CDCP2 c.1117+15G>A](/variant/cdcp2-c-1117-plus-15g-a), [CDCP2 c.1117+168C>G](/variant/cdcp2-c-1117-plus-168c-g), [CDCP2 c.1117+184C>T](/variant/cdcp2-c-1117-plus-184c-t).

### 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 3998745). 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.*