Is CDKN2A p.Arg107Ser (c.319C>A) pathogenic?

CDKN2A p.Arg107Ser (c.319C>A) is classified Uncertain significance in CDKN2A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-18). AlphaMissense: ambiguous (0.4114); Very rare (popmax 8.48e-05%, nfe); Associated with familial melanoma.

What condition is associated with CDKN2A p.Arg107Ser (c.319C>A)?

CDKN2A p.Arg107Ser (c.319C>A) is associated with familial melanoma, hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.Arg107Ser (c.319C>A) in the general population?

CDKN2A p.Arg107Ser (c.319C>A) is very rare (popmax 8.48e-05%, nfe) (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.Arg107Ser (c.319C>A)?

AlphaMissense predicts ambiguous (score 0.4114) — an in-silico prediction, not a clinical call.

CDKN2A p.Arg107Ser

c.319C>A · rs1554654024 · VCV463498

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4114 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

familial melanoma

Computational evidence

Protein change
AlphaMissense	0.4114	ambiguous
REVEL	0.508	indeterminate
SaProt	LLR -9.02	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP 2, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	21.4	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 8.48e-05% European (non-Finnish) · 1/1,179,342 alleles

Overall 6.88e-05% 1/1,453,408 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: CDKN2A
Protein: p.Arg107Ser
Coding: c.319C>A
MANE Select: NM_000077
dbSNP: rs1554654024
Type: single nucleotide variant
Location: chr9:21971040 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 107: a UniProt-annotated variant site (in cmm2); a UniProt-annotated variant site (in); 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: hereditary neoplastic syndrome

For Familial melanoma (Orphanet):

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

Similar variants

CDKN2A p.Arg107= Uncertain significance ★★ same residue
CDKN2A p.Arg107Pro Uncertain significance ★★ ⚠ same residue
CDKN2A p.Arg107Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A p.Arg107Gly Uncertain significance ★ ⚠ same residue
CDKN2A p.Arg107His Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A p.Arg107Leu Uncertain significance ★★ same residue
CDKN2A c.150+1G>A Likely pathogenic ★★ same condition
CDKN2A c.150+2T>G 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-arg107ser (accessed [today's date]).

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