Is CDKN2A p.His83Tyr (c.247C>T) pathogenic?

CDKN2A p.His83Tyr (c.247C>T) is classified Conflicting classifications of pathogenicity in CDKN2A (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-06-02). AlphaMissense: likely pathogenic (0.7859); Absent from gnomAD v4.1; Associated with familial melanoma.

What condition is associated with CDKN2A p.His83Tyr (c.247C>T)?

CDKN2A p.His83Tyr (c.247C>T) is associated with familial melanoma, melanoma and neural system tumor syndrome, melanoma-pancreatic cancer syndrome (ClinVar).

How common is CDKN2A p.His83Tyr (c.247C>T) in the general population?

CDKN2A p.His83Tyr (c.247C>T) is absent from gnomAD v4.1 (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.His83Tyr (c.247C>T)?

AlphaMissense predicts likely pathogenic (score 0.7859) — an in-silico prediction, not a clinical call.

CDKN2A p.His83Tyr

c.247C>T · rs121913385 · VCV376307

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.7859 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,604,272)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial melanoma

Computational evidence

Protein change
AlphaMissense	0.7859	likely pathogenic
REVEL	0.804	moderately pathogenic-leaning
SaProt	LLR -15.24	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 12	GERP 2, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	27.6	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 1,604,272). 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.His83Tyr
Coding: c.247C>T
MANE Select: NM_000077
dbSNP: rs121913385
Type: single nucleotide variant
Location: chr9:21971112 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 83: an α-helix; a UniProt-annotated variant site (in a lung tumor); a UniProt-annotated variant site (in); a UniProt-annotated variant site (in a pancreas tumor; also found in head and neck tumor); 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 melanoma-pancreatic cancer 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.His83= Conflicting classifications of pathogenicity ★ same residue
CDKN2A p.His83Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A p.His83Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A p.His83fs 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-his83tyr (accessed [today's date]).

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