# NM_001353655.3(CDCP2):c.1117G>C (p.Val373Leu)

https://sugi.bio/variant/cdcp2-p-val373leu

## Summary

**CDCP2 p.Val373Leu (c.1117G>C)** is classified **Uncertain significance** in CDCP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-20). AlphaMissense: likely benign (0.31); Very rare (popmax 0.00833%, amr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00833%, amr)

## 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.Val373Leu |
| Coding change (HGVS c.) | c.1117G>C |
| MANE Select transcript | [NM_001353655](https://www.ncbi.nlm.nih.gov/nuccore/NM_001353655) |
| Variant type | single nucleotide variant |
| Location | chr1:54139753-54139753 (GRCh38) |
| ClinVar | [VCV3998736](https://www.ncbi.nlm.nih.gov/clinvar/variation/3998736/) |

**All HGVS expressions:** `NC_000001.10:g.54605426C>G`, `NC_000001.11:g.54139753C>G`, `NM_001353655.3:c.1117G>C`, `NM_201546.5:c.1117G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.31)
- REVEL 0.409 (indeterminate)
- SpliceAI predicts **donor loss** (Δ 0.96) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.58, GERP 1.81, phastCons 1 — highly conserved (differs from AlphaMissense)
- **SaProt:** not scored — SaProt is structure-aware and AlphaFold DB has no model for this protein. That is a property of the dataset, not of the variant, and is not evidence either way.
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **G373R** vs ClinVar **V373L**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 25.6**. 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 **0.96**, acceptor gain **0.00**, donor gain **0.01**. Largest is donor loss at this position.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.01**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.74** (loss), gain 0.01 / loss 0.74. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00833%** (amr) · FAF95 0.00323% · FAF99 0.00206% · 5/60,014 in the highest group · 36/1,614,124 alleles overall — very rare (popmax 0.00833%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00833% | 12,003 |
| European (non-Finnish) | 0.00246% | 40,691 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,486 |
| African / African-American | 0.00133% | 74,944 |

*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}


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 2025-04-20.

**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 | 2025-04-20 |

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

## Similar variants {#similar}

Related CDCP2 variant pages (same residue, condition, or type): [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), [CDCP2 c.1117+97C>T](/variant/cdcp2-c-1117-plus-97c-t).

### 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 3998736). 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.*