# NM_001286577.2(C2CD3):c.1730G>A (p.Arg577His)

https://sugi.bio/variant/c2cd3-p-arg577his

## Summary

**C2CD3 p.Arg577His (c.1730G>A)** is classified **Likely pathogenic** in C2CD3 (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely benign (0.1117); Very rare (popmax 0.00167%, amr); Associated with orofaciodigital syndrome type 14.

**At a glance:** Likely pathogenic · review: No assertion criteria · rsID rs755686768 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the C2CD3 gene that is considered likely disease-causing, submitted by 1 submitter, 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.Arg577His |
| Coding change (HGVS c.) | c.1730G>A |
| MANE Select transcript | [NM_001286577](https://www.ncbi.nlm.nih.gov/nuccore/NM_001286577) |
| dbSNP | [rs755686768](https://www.ncbi.nlm.nih.gov/snp/rs755686768/) |
| Variant type | single nucleotide variant |
| Location | chr11:74114384-74114384 (GRCh38) |
| ClinVar | [VCV2585641](https://www.ncbi.nlm.nih.gov/clinvar/variation/2585641/) |

**All HGVS expressions:** `NC_000011.10:g.74114384C>T`, `NC_000011.9:g.73825429C>T`, `NG_041791.1:g.61636G>A`, `NM_001286577.2:c.1730G>A`, `NM_015531.6:c.1730G>A`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — AlphaMissense predicts likely-benign.

- AlphaMissense **likely benign** (0.1117) — ⚠ discordant with the pathogenic call
- REVEL 0.156 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.1 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor loss** (Δ 0.69) — consistent with the pathogenic call
- Conservation: phyloP 5.921, GERP 1.91, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 29.2**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.69**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss at this position.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  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**0.71** (loss), gain 0.37 / loss 0.71. 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 **0.00167%** (amr) · FAF95 0.000616% · FAF99 0.000475% · 1/59,854 in the highest group · 15/1,611,260 alleles overall — very rare (popmax 0.00167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00167% | 59,854 |
| African / African-American | 0.00133% | 74,964 |
| European (non-Finnish) | 0.0011% | 90,606 |

*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 **577** lies in the c2 1 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}

**Likely pathogenic** — review status No assertion criteria *(no assertion criteria provided)*.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Department of Pediatrics, National Cheng-Kung University Hospital | Likely pathogenic | no assertion criteria provided | clinical testing |  |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Orofaciodigital syndrome type 14, 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 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2585641). 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.*