# NM_015500.2(C2CD2):c.1287C>T (p.Val429=)

https://sugi.bio/variant/c2cd2-p-val429

## Summary

**C2CD2 p.Val429= (c.1287C>T)** is classified **Benign** in C2CD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-03-29). Rare (popmax 0.949%, afr).

**At a glance:** Benign · review: Single submitter · rsID rs77424551 · 1 submitter · rare (popmax 0.949%, afr)

## For patients & families {#patients}

This is a change in the C2CD2 gene that is classified as benign — not considered disease-causing, 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.Val429= |
| Coding change (HGVS c.) | c.1287C>T |
| MANE Select transcript | [NM_015500](https://www.ncbi.nlm.nih.gov/nuccore/NM_015500) |
| dbSNP | [rs77424551](https://www.ncbi.nlm.nih.gov/snp/rs77424551/) |
| Variant type | single nucleotide variant |
| Location | chr21:41907023-41907023 (GRCh38) |
| ClinVar | [VCV777621](https://www.ncbi.nlm.nih.gov/clinvar/variation/777621/) |

**All HGVS expressions:** `NC_000021.8:g.43327132G>A`, `NC_000021.9:g.41907023G>A`, `NM_015500.2:c.1287C>T`, `NM_199050.3:c.822C>T`

## Computational & population evidence {#evidence}

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

- **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 -2.061, GERP -4.25 — fast-evolving / accelerated position
- CADD: **PHRED 0.617**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.21 donor loss), 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 **0.949%** (afr) · FAF95 0.892% · FAF99 0.868% · 712/75,002 in the highest group · 757/1,613,990 alleles overall — rare (popmax 0.949%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.949% | 105 |
| Remaining individuals (not grpmax-eligible) | 0.0304% | 3,289 |
| Admixed American | 0.02% | 5,001 |
| Middle Eastern | 0.0167% | 6,006 |
| East Asian | 0.00223% | 44,882 |
| South Asian | 0.0022% | 45,538 |
| European (non-Finnish) | 0.000847% | 117,997 |

*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}


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

## Clinical significance {#significance}

**Benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-03-29.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2018-03-29 |

**Reported phenotype names (ClinVar):** not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Similar variants {#similar}

Related C2CD2 variant pages (same residue, condition, or type): [C2CD2 p.Pro104=](/variant/c2cd2-p-pro104), [C2CD2 p.Ala123Val](/variant/c2cd2-p-ala123val), [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).

### 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 777621). 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.*