Is CDKN2C p.Ala77Glu (c.230C>A) pathogenic?

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.

What condition is associated with CDKN2C p.Ala77Glu (c.230C>A)?

CDKN2C p.Ala77Glu (c.230C>A) is associated with plasma cell myeloma (ClinVar).

How common is CDKN2C p.Ala77Glu (c.230C>A) in the general population?

CDKN2C p.Ala77Glu (c.230C>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Multiple myeloma inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CDKN2C p.Ala77Glu (c.230C>A)?

AlphaMissense predicts likely pathogenic (score 0.9768) — an in-silico prediction, not a clinical call.

CDKN2C p.Ala77Glu

c.230C>A · rs746646631 · VCV800342

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9768 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

plasma cell myeloma

Computational evidence

Protein change
AlphaMissense	0.9768	likely pathogenic ✓ concordant with ClinVar · top 5% in CDKN2C
REVEL	0.844	moderately pathogenic-leaning
SaProt	LLR -12.58	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 3,898 bp · p 0.00048 · regional, not allelic
Overall
CADD	27.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,028 alleles

Overall 6.84e-05% 1/1,461,894 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CDKN2C
Protein: p.Ala77Glu
Coding: c.230C>A
MANE Select: NM_078626
dbSNP: rs746646631
Type: single nucleotide variant
Location: chr1:50973993 (GRCh38)
Gene constraint: LOEUF 0.94 · pLI 0.21 (gnomAD)
Structure: AlphaFold pLDDT 92.36 · 6 PDB
Residue 77: an α-helix

Full CDKN2C gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

plasma cell myeloma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Multiple myeloma (Orphanet):

Inheritance: Not applicable
Onset: Adult
Prevalence: 1-9 / 100 000 (United States)

Similar variants

CDKN2C p.Ala77Val Uncertain significance ★ ⚠ same residue
CDKN2C p.Ala77= Likely benign ★ same residue
CDKN2C p.Asn159= Likely benign ★★ same type
CDKN2C p.Ala127Asp Uncertain significance ★ ⚠ same type
CDKN2C p.Ala161Gly Uncertain significance ★ ⚠ same type
CDKN2C p.Arg39Ser Uncertain significance ★ ⚠ same type
CDKN2C p.Asp17His Uncertain significance ★ ⚠ same type
CDKN2C p.Asp17Tyr Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cdkn2c-p-ala77glu (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown