Is CDKN2A p.Tyr129His (c.385T>C) pathogenic?

CDKN2A p.Tyr129His (c.385T>C) is classified Uncertain significance in CDKN2A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-05-23). AlphaMissense: likely pathogenic (0.8201); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Tyr129His (c.385T>C)?

CDKN2A p.Tyr129His (c.385T>C) is associated with hereditary neoplastic syndrome, melanoma and neural system tumor syndrome, familial melanoma (ClinVar).

How common is CDKN2A p.Tyr129His (c.385T>C) in the general population?

CDKN2A p.Tyr129His (c.385T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDKN2A p.Tyr129His (c.385T>C)?

AlphaMissense predicts likely pathogenic (score 0.8201) — an in-silico prediction, not a clinical call.

CDKN2A p.Tyr129His

c.385T>C · rs1554653923 · VCV1735601

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8201 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.8201	likely pathogenic
REVEL	0.72	pathogenic-leaning
SaProt	LLR -8.84	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	24.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CDKN2A
Protein: p.Tyr129His
Coding: c.385T>C
MANE Select: NM_000077
dbSNP: rs1554653923
Type: single nucleotide variant
Location: chr9:21970974 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 129: an α-helix; the 'disordered' region

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: melanoma and neural system tumor syndrome familial melanoma

Similar variants

CDKN2A p.Tyr129Ter Pathogenic ★★ same residue
CDKN2A p.Tyr129= Likely benign ★★ same residue
CDKN2A p.Tyr129Asp Uncertain significance ★ ⚠ same residue
CDKN2A p.Tyr129fs 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-tyr129his (accessed [today's date]).

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