Is CDKN2A p.Ser56Arg (c.168C>A) pathogenic?

CDKN2A p.Ser56Arg (c.168C>A) is classified Uncertain significance in CDKN2A (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-06-03). AlphaMissense: likely pathogenic (0.863); No allele count reported in gnomAD v4.1 (AN 1,597,576); Associated with familial melanoma.

What condition is associated with CDKN2A p.Ser56Arg (c.168C>A)?

CDKN2A p.Ser56Arg (c.168C>A) is associated with familial melanoma, melanoma and neural system tumor syndrome, hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.Ser56Arg (c.168C>A) in the general population?

CDKN2A p.Ser56Arg (c.168C>A) is no allele count reported in gnomAD v4.1 (AN 1,597,576) (gnomAD).

How is Familial melanoma inherited?

Typically Autosomal dominant, Multigenic/multifactorial (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CDKN2A p.Ser56Arg (c.168C>A)?

AlphaMissense predicts likely pathogenic (score 0.863) — an in-silico prediction, not a clinical call.

CDKN2A p.Ser56Arg

c.168C>A · rs771138120 · VCV236981

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.863 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,597,576)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

familial melanoma

Computational evidence

Protein change
AlphaMissense	0.863	likely pathogenic
REVEL	0.42	indeterminate
SaProt	LLR -7.88	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2	GERP 0.25, phastCons 0.014
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	21.9	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

No allele count reported in gnomAD v4.1 (AN 1,597,576). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CDKN2A
Protein: p.Ser56Arg
Coding: c.168C>A
MANE Select: NM_000077
dbSNP: rs771138120
Type: single nucleotide variant
Location: chr9:21971191 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 56: a UniProt-annotated variant site (in cmm2); the 'interaction with cdk5rap3 and mdm2' region; the 'disordered' region

Full CDKN2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial melanoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: melanoma and neural system tumor syndrome hereditary neoplastic syndrome

For Familial melanoma (Orphanet):

Inheritance: Autosomal dominant, Multigenic/multifactorial
Onset: Adult
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

CDKN2A p.Ser56Ile Pathogenic/Likely pathogenic ★★ same residue
CDKN2A p.Gly56Arg Uncertain significance ★★ same residue
CDKN2A p.Ser56Asn Uncertain significance ★★ ⚠ same residue
CDKN2A p.Gly56= Benign/Likely benign ★★ same residue
CDKN2A p.Ser56= Conflicting classifications of pathogenicity ★ same residue
CDKN2A p.Ser56Gly Uncertain significance ★ ⚠ same residue
CDKN2A p.Ser56fs Pathogenic ★ same residue
CDKN2A c.150+1G>A Likely pathogenic ★★ same condition

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/cdkn2a-p-ser56arg (accessed [today's date]).

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