# NM_001286577.2(C2CD3):c.373C>G (p.Pro125Ala)

https://sugi.bio/variant/c2cd3-p-pro125ala

## Summary

**C2CD3 p.Pro125Ala (c.373C>G)** is classified **Uncertain significance** in C2CD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-16). AlphaMissense: likely benign (0.1734); Ultra-rare (popmax 0.0166%, mid); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.0166%, mid)

## 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 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 | [C2CD3](https://sugi.bio/atlas/gene/C2CD3/) |
| Protein change (HGVS p.) | p.Pro125Ala |
| Coding change (HGVS c.) | c.373C>G |
| MANE Select transcript | [NM_001286577](https://www.ncbi.nlm.nih.gov/nuccore/NM_001286577) |
| Variant type | single nucleotide variant |
| Location | chr11:74161509-74161509 (GRCh38) |
| ClinVar | [VCV3262453](https://www.ncbi.nlm.nih.gov/clinvar/variation/3262453/) |

**All HGVS expressions:** `NC_000011.10:g.74161509G>C`, `NC_000011.9:g.73872554G>C`, `NG_041791.1:g.14511C>G`, `NM_001286577.2:c.373C>G`, `NM_015531.6:c.373C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1734)
- REVEL 0.658 (pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -7.665 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** REVEL calls this damaging; AlphaMissense and SaProt do not
- Conservation: phyloP 9.606, GERP 1.91, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 25.0**. 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.*
- 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 (G>A, Δ0.21 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 **0.0166%** (mid) · FAF95 6.8e-05% · FAF99 1.9e-05% · 1/6,008 in the highest group · 4/1,441,380 alleles overall — ultra-rare (popmax 0.0166%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0166% | 6,008 |
| European (non-Finnish) | 0.000256% | 389,897 |

*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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-05-16.

**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 | 2024-05-16 |

## 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 C2CD3 variant pages (same residue, condition, or type): [C2CD3 c.2085+5G>A](/variant/c2cd3-c-2085-plus-5g-a), [C2CD3 c.4951+6C>T](/variant/c2cd3-c-4951-plus-6c-t), [C2CD3 p.Ala1382Pro](/variant/c2cd3-p-ala1382pro), [C2CD3 p.Ala1777Thr](/variant/c2cd3-p-ala1777thr), [C2CD3 p.Ala95Thr](/variant/c2cd3-p-ala95thr), [C2CD3 p.Arg1122Ile](/variant/c2cd3-p-arg1122ile), [C2CD3 p.Arg1145His](/variant/c2cd3-p-arg1145his), [C2CD3 p.Arg1183His](/variant/c2cd3-p-arg1183his).

### 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 3262453). 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.*