# NM_001378964.1(CDON):c.3588C>T (p.Asp1196=)

https://sugi.bio/variant/cdon-p-asp1196

## Summary

**CDON p.Asp1196= (c.3588C>T)** is classified **Benign** in CDON (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-17). Low-frequency (popmax 1.8%, afr); Associated with holoprosencephaly 11.

**At a glance:** Benign · review: Multiple submitters · rsID rs140895899 · 4 submitters · 1 linked condition · low-frequency (popmax 1.8%, afr)

## For patients & families {#patients}

This is a change in the CDON gene that is classified as benign — not considered disease-causing, submitted by 4 submitters, and is linked to holoprosencephaly 11.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024938/index) · [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.Asp1196= |
| Coding change (HGVS c.) | c.3588C>T |
| MANE Select transcript | [NM_001378964](https://www.ncbi.nlm.nih.gov/nuccore/NM_001378964) |
| dbSNP | [rs140895899](https://www.ncbi.nlm.nih.gov/snp/rs140895899/) |
| Variant type | single nucleotide variant |
| Location | chr11:125961767-125961767 (GRCh38) |
| ClinVar | [VCV303491](https://www.ncbi.nlm.nih.gov/clinvar/variation/303491/) |

**All HGVS expressions:** `NC_000011.10:g.125961767G>A`, `NC_000011.9:g.125831662G>A`, `NG_029776.1:g.106526C>T`, `NM_001243597.3:c.3588C>T`, `NM_001378964.1:c.3588C>T`, `NM_016952.6:c.3588C>T`

## Computational & population evidence {#evidence}

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

- **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 -0.362, GERP -2.19 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 4.342**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.69 donor 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 **1.8%** (afr) · FAF95 1.72% · FAF99 1.69% · 1,352/75,022 in the highest group · 1,594/1,614,040 alleles overall — low-frequency (popmax 1.8%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 1.8% | 55 |
| Admixed American | 0.15% | 667 |
| Remaining individuals (not grpmax-eligible) | 0.13% | 772 |
| Middle Eastern | 0.099% | 1,010 |
| South Asian | 0.00879% | 11,383 |
| East Asian | 0.00668% | 14,961 |
| European (non-Finnish) | 0.00458% | 21,851 |

*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}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-17.

**Submitter consensus:** unanimous (4/4 Benign).

**Submission history:** 4 submissions (2018–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Benign | criteria provided, single submitter | clinical testing | 2023-11-06 |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2019-04-18 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-12-17 |

## Associated conditions {#conditions}

[holoprosencephaly 11](https://sugi.bio/atlas/disease/holoprosencephaly-11/).

**Reported phenotype names (ClinVar):** Holoprosencephaly 11, CDON-related disorder, CDON-related condition.

## Similar variants {#similar}

Related CDON variant pages (same residue, condition, or type): [CDON c.3276+1G>T](/variant/cdon-c-3276-plus-1g-t), [CDON c.640+1G>A](/variant/cdon-c-640-plus-1g-a), [CDON c.*1805A>G](/variant/cdon-c-star-1805a-g), [CDON c.*1816C>T](/variant/cdon-c-star-1816c-t), [CDON c.*2349A>C](/variant/cdon-c-star-2349a-c), [CDON c.*2377T>C](/variant/cdon-c-star-2377t-c), [CDON c.*2760A>G](/variant/cdon-c-star-2760a-g), [CDON p.Ala1099Val](/variant/cdon-p-ala1099val).

### 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 303491). 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.*