# NM_001378964.1(CDON):c.3004C>T (p.Pro1002Ser)

https://sugi.bio/variant/cdon-p-pro1002ser

## Summary

**CDON p.Pro1002Ser (c.3004C>T)** is classified **Uncertain significance** in CDON (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-23). AlphaMissense: ambiguous (0.3914); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense ambiguous · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the CDON gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, 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 | [CDON](https://sugi.bio/atlas/gene/CDON/) |
| Protein change (HGVS p.) | p.Pro1002Ser |
| Coding change (HGVS c.) | c.3004C>T |
| MANE Select transcript | [NM_001378964](https://www.ncbi.nlm.nih.gov/nuccore/NM_001378964) |
| Variant type | single nucleotide variant |
| Location | chr11:125981321-125981321 (GRCh38) |
| ClinVar | [VCV4839843](https://www.ncbi.nlm.nih.gov/clinvar/variation/4839843/) |

**All HGVS expressions:** `NC_000011.10:g.125981321G>A`, `NC_000011.9:g.125851216G>A`, `NG_029776.1:g.86972C>T`, `NM_001243597.3:c.3004C>T`, `NM_001378964.1:c.3004C>T`, `NM_001441161.1:c.3004C>T`, `NM_001441162.1:c.3004C>T`, `NM_001441163.1:c.3004C>T`, `NM_001441164.1:c.3004C>T`, `NM_001441165.1:c.3004C>T`, `NM_001441166.1:c.3004C>T`, `NM_016952.6:c.3004C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL make no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.3914) — no call either way
- REVEL 0.312 (indeterminate)
- SaProt LLR -5.716 (tolerated)
- SpliceAI predicts **acceptor gain** (Δ 0.25) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.828, GERP 2.03, phastCons 1 — highly conserved
- CADD: **PHRED 28.3**. 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 0.93** across the covering region of the MANE Select transcript (125,960,945–126,023,476), spanning 62,531 bp. Chi-square p 0.0032. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.01**, donor loss **0.00**, acceptor gain **0.25**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.01**, donor loss **0.00**, acceptor gain **0.25**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.00167%** (amr) · FAF95 6.8e-05% · FAF99 1.9e-05% · 1/59,990 in the highest group · 4/1,460,756 alleles overall — very rare (popmax 0.00167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00167% | 59,990 |
| European (non-Finnish) | 0.000254% | 393,323 |

*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}

**CDON** population constraint: LOEUF 0.733, pLI 4.8789e-12, missense-Z 1.7698. *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 62.62, 11% of residues very-high.

**3 experimental structure(s)** (PDB): [3D1M](https://www.rcsb.org/structure/3D1M), [3N1F](https://www.rcsb.org/structure/3N1F), [3N1Q](https://www.rcsb.org/structure/3N1Q).

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

*Describes the biological roles of CDON (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:** CDON's established molecular role includes coreceptor activity.


### Pathways affected {#pathways}

CDON participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activation of SMO](https://reactome.org/content/detail/R-HSA-5635838) | curated |
| [Ligand-receptor interactions](https://reactome.org/content/detail/R-HSA-5632681) | curated |
| [Myogenesis](https://reactome.org/content/detail/R-HSA-525793) | electronic |

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

**Molecular function:** coreceptor activity.

**Biological process:** smoothened signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2026-02-23.

**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 | 2026-02-23 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related CDON variant pages (same residue, condition, or type): [CDON p.Pro1002Ala](/variant/cdon-p-pro1002ala), [CDON p.Ala1099Val](/variant/cdon-p-ala1099val), [CDON p.Ala495Val](/variant/cdon-p-ala495val), [CDON p.Arg157Trp](/variant/cdon-p-arg157trp), [CDON p.Arg760Leu](/variant/cdon-p-arg760leu), [CDON p.Asn1222Asp](/variant/cdon-p-asn1222asp), [CDON p.Gln1008Lys](/variant/cdon-p-gln1008lys), [CDON p.Glu663Asp](/variant/cdon-p-glu663asp).

### 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 4839843). 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.*