# NM_001286577.2(C2CD3):c.2504A>T (p.Lys835Ile)

https://sugi.bio/variant/c2cd3-p-lys835ile

## Summary

**C2CD3 p.Lys835Ile (c.2504A>T)** is classified **Uncertain significance** in C2CD3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-09). AlphaMissense: likely pathogenic (0.8743); Ultra-rare (popmax 0.015%, amr); Associated with orofaciodigital syndrome type 14.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs779366546 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · ultra-rare (popmax 0.015%, amr)

## For patients & families {#patients}

This is a change in the C2CD3 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to orofaciodigital syndrome type 14.

*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/0013655/index) · [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.Lys835Ile |
| Coding change (HGVS c.) | c.2504A>T |
| MANE Select transcript | [NM_001286577](https://www.ncbi.nlm.nih.gov/nuccore/NM_001286577) |
| dbSNP | [rs779366546](https://www.ncbi.nlm.nih.gov/snp/rs779366546/) |
| Variant type | single nucleotide variant |
| Location | chr11:74103207-74103207 (GRCh38) |
| ClinVar | [VCV1311851](https://www.ncbi.nlm.nih.gov/clinvar/variation/1311851/) |

**All HGVS expressions:** `NC_000011.10:g.74103207T>A`, `NC_000011.9:g.73814252T>A`, `NG_041791.1:g.72813A>T`, `NM_001286577.2:c.2504A>T`, `NM_015531.6:c.2504A>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8743)
- REVEL 0.821 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -9.04 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL call this damaging; SaProt does not
- Conservation: phyloP 7.873, GERP 1.91, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 7%** most-pathogenic-predicted substitutions in C2CD3 (of 13,773 modeled).
- CADD: **PHRED 26.6**. 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 (74,013,388–74,170,792), spanning 157,404 bp. Chi-square p 9.8e-06. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (T>C, Δ0.36 acceptor 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 **0.015%** (amr) · FAF95 0.00773% · FAF99 0.00578% · 9/60,014 in the highest group · 9/1,614,090 alleles overall — ultra-rare (popmax 0.015%, amr).

*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}

Residue **835** lies in the c2 2 domain.

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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-09.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-07-22 |
| 3billion | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-12-09 |

## Associated conditions {#conditions}

[orofaciodigital syndrome type 14](https://sugi.bio/atlas/disease/orofaciodigital-syndrome-type-14/).

**Reported phenotype names (ClinVar):** Orofaciodigital syndrome type 14, not provided, none provided, Orofaciodigital syndrome xiv.

## Similar variants {#similar}

Related C2CD3 variant pages (same residue, condition, or type): [C2CD3 c.3911-2A>T](/variant/c2cd3-c-3911-minus-2a-t), [C2CD3 p.Arg621Ter](/variant/c2cd3-p-arg621ter), [C2CD3 p.Arg666Ter](/variant/c2cd3-p-arg666ter), [C2CD3 c.5495+4A>G](/variant/c2cd3-c-5495-plus-4a-g), [C2CD3 c.5882-332A>G](/variant/c2cd3-c-5882-minus-332a-g), [C2CD3 p.Arg1061Thr](/variant/c2cd3-p-arg1061thr), [C2CD3 p.Arg1248Cys](/variant/c2cd3-p-arg1248cys), [C2CD3 p.Arg1553Gln](/variant/c2cd3-p-arg1553gln).

### 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 1311851). 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.*