# NM_015500.2(C2CD2):c.368C>T (p.Ala123Val)

https://sugi.bio/variant/c2cd2-p-ala123val

## Summary

**C2CD2 p.Ala123Val (c.368C>T)** is classified **Uncertain significance** in C2CD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-09). AlphaMissense: likely benign (0.0978); Ultra-rare (popmax 0.026%, afr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs201798564 · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.026%, afr)

## For patients & families {#patients}

This is a change in the C2CD2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [C2CD2](https://sugi.bio/atlas/gene/C2CD2/) |
| Protein change (HGVS p.) | p.Ala123Val |
| Coding change (HGVS c.) | c.368C>T |
| MANE Select transcript | [NM_015500](https://www.ncbi.nlm.nih.gov/nuccore/NM_015500) |
| dbSNP | [rs201798564](https://www.ncbi.nlm.nih.gov/snp/rs201798564/) |
| Variant type | single nucleotide variant |
| Location | chr21:41942157-41942157 (GRCh38) |
| ClinVar | [VCV2235571](https://www.ncbi.nlm.nih.gov/clinvar/variation/2235571/) |

**All HGVS expressions:** `NC_000021.8:g.43362266G>A`, `NC_000021.9:g.41942157G>A`, `NM_015500.2:c.368C>T`, `NM_198997.1:c.368C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0978)
- REVEL 0.027 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -2.605 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor gain** (Δ 0.39) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 4.778, GERP -0.631, phastCons 0.943 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 18.56**. 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 0.87** across the covering region of the MANE Select transcript (41,889,127–41,953,648), spanning 64,521 bp. Chi-square p 0.00014. 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 **0.27**, acceptor gain **0.00**, donor gain **0.39**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.27**, acceptor gain **0.00**, donor gain **0.39**.
- Pangolin: Δ**0.27** (gain), gain 0.27 / loss 0.17. 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 **0.026%** (afr) · FAF95 0.017% · FAF99 0.0141% · 19/73,022 in the highest group · 37/1,549,244 alleles overall — ultra-rare (popmax 0.026%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.026% | 3,843 |
| East Asian | 0.0244% | 4,092 |
| Remaining individuals (not grpmax-eligible) | 0.00334% | 29,961 |
| South Asian | 0.00119% | 83,942 |
| European (non-Finnish) | 0.000436% | 229,358 |

*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}

**C2CD2** population constraint: LOEUF 0.924, pLI 2.4855e-09, missense-Z 0.77398. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **123** lies in the smp-lbd domain.

AlphaFold model confidence (whole protein): pLDDT 62.52, 8% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-07-09.

**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 | 2021-07-09 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related C2CD2 variant pages (same residue, condition, or type): [C2CD2 p.Pro104=](/variant/c2cd2-p-pro104), [C2CD2 p.Ala136Gly](/variant/c2cd2-p-ala136gly), [C2CD2 p.Ala146Val](/variant/c2cd2-p-ala146val), [C2CD2 p.Ala189Thr](/variant/c2cd2-p-ala189thr), [C2CD2 p.Ala207Val](/variant/c2cd2-p-ala207val), [C2CD2 p.Ala345Val](/variant/c2cd2-p-ala345val), [C2CD2 p.Ala466Thr](/variant/c2cd2-p-ala466thr), [C2CD2 p.Ala492Val](/variant/c2cd2-p-ala492val).

### 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 2235571). 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.*