# NM_078626.3(CDKN2C):c.230C>A (p.Ala77Glu)

https://sugi.bio/variant/cdkn2c-p-ala77glu

## Summary

**CDKN2C p.Ala77Glu (c.230C>A)** is classified **Likely pathogenic** in CDKN2C (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-08-31). AlphaMissense: likely pathogenic (0.9768); Very rare (popmax 8.47e-05%, nfe); Associated with plasma cell myeloma.

**At a glance:** Likely pathogenic · review: No assertion criteria · rsID rs746646631 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the CDKN2C gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to plasma cell myeloma.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Not applicable |
| Age of onset (of this condition) | Adult |
| Prevalence | 1-9 / 100 000 (United States) |
| Clinical trials | 3025 registered for this condition — see ClinicalTrials.gov |

**Commonly reported features of Multiple myeloma** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Osteopenia — Very frequent (99-80%)
- Pathologic fracture — Very frequent (99-80%)
- Nephrotic syndrome — Frequent (79-30%)
- Nephropathy — Frequent (79-30%)
- Pallor — Frequent (79-30%)
- Anemia — Frequent (79-30%)
- Acute kidney injury — Frequent (79-30%)
- Hyperproteinemia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007108/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CDKN2C](https://sugi.bio/atlas/gene/CDKN2C/) |
| Protein change (HGVS p.) | p.Ala77Glu |
| Coding change (HGVS c.) | c.230C>A |
| MANE Select transcript | [NM_078626](https://www.ncbi.nlm.nih.gov/nuccore/NM_078626) |
| dbSNP | [rs746646631](https://www.ncbi.nlm.nih.gov/snp/rs746646631/) |
| Variant type | single nucleotide variant |
| Location | chr1:50973993-50973993 (GRCh38) |
| ClinVar | [VCV800342](https://www.ncbi.nlm.nih.gov/clinvar/variation/800342/) |

**All HGVS expressions:** `NC_000001.10:g.51439665C>A`, `NC_000001.11:g.50973993C>A`, `NM_001262.3:c.230C>A`, `NM_078626.3:c.230C>A`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9768) — concordant with the pathogenic call
- REVEL 0.844 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.583 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 6.006, GERP 1.73, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 5%** most-pathogenic-predicted substitutions in CDKN2C (of 982 modeled).
- CADD: **PHRED 27.4**. 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 0.76** across the covering region of the MANE Select transcript (50,970,369–50,974,267), spanning 3,898 bp. Chi-square p 0.00048. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **8.47e-05%** (nfe) · 1/1,180,028 in the highest group · 1/1,461,894 alleles overall — very rare (popmax 8.47e-05%, nfe).

*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}

**CDKN2C** population constraint: LOEUF 0.94, pLI 0.21445, missense-Z 1.5054. *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 **77** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 92.36, 85% of residues very-high.

**6 experimental structure(s)** (PDB): [1BU9](https://www.rcsb.org/structure/1BU9), [1G3N](https://www.rcsb.org/structure/1G3N), [1IHB](https://www.rcsb.org/structure/1IHB), [1MX2](https://www.rcsb.org/structure/1MX2), [1MX4](https://www.rcsb.org/structure/1MX4), [1MX6](https://www.rcsb.org/structure/1MX6) — incl. mutant structure 1MX2.

## What this gene does {#gene-function}

*Describes the biological roles of CDKN2C (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.*

**How this variant is thought to act:** CDKN2C's established molecular role includes cyclin-dependent protein serine/threonine kinase inhibitor activity.


### Pathways affected {#pathways}

CDKN2C participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cyclin D associated events in G1](https://reactome.org/content/detail/R-HSA-69231) | curated |
| [Oncogene Induced Senescence](https://reactome.org/content/detail/R-HSA-2559585) | curated |
| [Oxidative Stress Induced Senescence](https://reactome.org/content/detail/R-HSA-2559580) | curated |
| [Senescence-Associated Secretory Phenotype (SASP)](https://reactome.org/content/detail/R-HSA-2559582) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** cyclin-dependent protein serine/threonine kinase inhibitor activity, protein kinase binding.

**Biological process:** negative regulation of cell population proliferation, negative regulation of cell growth, regulation of G1/S transition of mitotic cell cycle.

## Clinical significance {#significance}

**Likely pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2019-08-31.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Xiao lab, Department of Pathology, Memorial Sloan Kettering Cancer Center | Likely pathogenic | no assertion criteria provided | clinical testing | 2019-08-31 |

## Associated conditions {#conditions}

[plasma cell myeloma](https://sugi.bio/atlas/disease/plasma-cell-myeloma/).

**Reported phenotype names (ClinVar):** Multiple myeloma, Plasma cell myeloma, Multiple myeloma, somatic.

## Similar variants {#similar}

Related CDKN2C variant pages (same residue, condition, or type): [CDKN2C p.Ala77Val](/variant/cdkn2c-p-ala77val), [CDKN2C p.Ala77=](/variant/cdkn2c-p-ala77), [CDKN2C p.Asn159=](/variant/cdkn2c-p-asn159), [CDKN2C p.Ala127Asp](/variant/cdkn2c-p-ala127asp), [CDKN2C p.Ala161Gly](/variant/cdkn2c-p-ala161gly), [CDKN2C p.Arg39Ser](/variant/cdkn2c-p-arg39ser), [CDKN2C p.Asp17His](/variant/cdkn2c-p-asp17his), [CDKN2C p.Asp17Tyr](/variant/cdkn2c-p-asp17tyr).

### 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 800342). 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.*