Is CDKN2A p.Arg103Trp (c.307C>T) pathogenic?

CDKN2A p.Arg103Trp (c.307C>T) is classified Uncertain significance in CDKN2A (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.2676); Very rare (popmax 0.0022%, sas); Associated with melanoma and neural system tumor syndrome.

What condition is associated with CDKN2A p.Arg103Trp (c.307C>T)?

CDKN2A p.Arg103Trp (c.307C>T) is associated with melanoma and neural system tumor syndrome, melanoma, cutaneous malignant, susceptibility to, 2, melanoma-pancreatic cancer syndrome (ClinVar).

How common is CDKN2A p.Arg103Trp (c.307C>T) in the general population?

CDKN2A p.Arg103Trp (c.307C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

How is Melanoma and neural system tumor syndrome inherited?

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

What do computational predictors say about CDKN2A p.Arg103Trp (c.307C>T)?

AlphaMissense predicts likely benign (score 0.2676) — an in-silico prediction, not a clinical call.

CDKN2A p.Arg103Trp

c.307C>T · rs767642535 · VCV423630

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2676 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

melanoma and neural system tumor syndrome

Computational evidence

Protein change
AlphaMissense	0.2676	likely benign
REVEL	0.313	indeterminate
SaProt	LLR -10.97	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 0.057, phastCons 0.057
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	22.3	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 0.0022% South Asian · 2/90,936 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000748% 12/1,605,324 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,468
African / African-American	0.00134%	74,882
European (non-Finnish)	0.000763%	131,037

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.Arg103Trp
Coding: c.307C>T
MANE Select: NM_000077
dbSNP: rs767642535
Type: single nucleotide variant
Location: chr9:21971052 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 103: the 'disordered' region

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

Disease context

melanoma and neural system tumor syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: melanoma, cutaneous malignant, susceptibility to, 2 melanoma-pancreatic cancer syndrome hereditary neoplastic syndrome familial melanoma

For Melanoma and neural system tumor syndrome (Orphanet):

Inheritance: Autosomal dominant, Unknown
Onset: Adult, Elderly

Similar variants

CDKN2A p.Arg103Gln Uncertain significance ★★ ⚠ same residue
CDKN2A p.Arg103Pro Uncertain significance ★★ ⚠ same residue
CDKN2A p.Arg103= Likely benign ★ same residue
CDKN2A p.Arg103fs Pathogenic ★★ same residue
CDKN2A c.150+1G>A Likely pathogenic ★★ same condition
CDKN2A c.150+2T>G Likely pathogenic ★★ same condition
CDKN2A c.151-1G>A Pathogenic ★★ same condition
CDKN2A c.151-1G>C 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-arg103trp (accessed [today's date]).

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