# NM_001286577.2(C2CD3):c.1201del (p.Gln401fs)

https://sugi.bio/variant/c2cd3-p-gln401fs

## Summary

**C2CD3 p.Gln401fs (c.1201del)** is classified **Pathogenic** in C2CD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-01). Very rare (popmax 0.000254%, nfe).

**At a glance:** Pathogenic · review: Single submitter · rsID rs1356626353 · 1 submitter · very rare (popmax 0.000254%, nfe)

## For patients & families {#patients}

This is a change in the C2CD3 gene that is reported as disease-causing, but on limited review, 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 | [C2CD3](https://sugi.bio/atlas/gene/C2CD3/) |
| Protein change (HGVS p.) | p.Gln401fs |
| Coding change (HGVS c.) | c.1201del |
| MANE Select transcript | [NM_001286577](https://www.ncbi.nlm.nih.gov/nuccore/NM_001286577) |
| dbSNP | [rs1356626353](https://www.ncbi.nlm.nih.gov/snp/rs1356626353/) |
| Variant type | Deletion |
| Location | chr11:74132860-74132860 (GRCh38) |
| ClinVar | [VCV3025764](https://www.ncbi.nlm.nih.gov/clinvar/variation/3025764/) |

**All HGVS expressions:** `NC_000011.10:g.74132860del`, `NC_000011.9:g.73843905del`, `NG_041791.1:g.43160del`, `NM_001286577.2:c.1201del`, `NM_015531.6:c.1201del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 7.85, GERP 1.43, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.637, pLI 1.8824e-14. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 7 of 33**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 34.0**. 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: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000254%** (nfe) · FAF95 6.8e-05% · FAF99 1.9e-05% · 3/1,179,854 in the highest group · 3/1,613,622 alleles overall — very rare (popmax 0.000254%, nfe).

*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}

**C2CD3** population constraint: LOEUF 0.637, pLI 1.8824e-14, missense-Z 2.6212. *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):

- **orofaciodigital syndrome type 14** — Definitive (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 55.65, 3% of residues very-high.

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

*Describes the biological roles of C2CD3 (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.*


### Pathways affected {#pathways}

C2CD3 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Anchoring of the basal body to the plasma membrane](https://reactome.org/content/detail/R-HSA-5620912) | curated |

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

**Biological process:** centriole elongation, protein localization to centrosome, non-motile cilium assembly.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-12-01.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Pathogenic | criteria provided, single submitter | clinical testing | 2023-12-01 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related C2CD3 variant pages (same residue, condition, or type): [C2CD3 c.708-2_708-1del](/variant/c2cd3-c-708-minus-2-708-minus-1del), [C2CD3 p.Ala913fs](/variant/c2cd3-p-ala913fs), [C2CD3 c.5496-6del](/variant/c2cd3-c-5496-minus-6del), [C2CD3 c.5496-7_5496-6del](/variant/c2cd3-c-5496-minus-7-5496-minus-6del), [C2CD3 c.1962+1del](/variant/c2cd3-c-1962-plus-1del), [C2CD3 c.708-2del](/variant/c2cd3-c-708-minus-2del), [C2CD3 p.Arg844fs](/variant/c2cd3-p-arg844fs), [C2CD3 p.Cys1114fs](/variant/c2cd3-p-cys1114fs).

### 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 3025764). 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.*