Is CDKN2A p.Leu78Pro (c.233T>C) pathogenic?

CDKN2A p.Leu78Pro (c.233T>C) is classified Uncertain significance in CDKN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-07). AlphaMissense: ambiguous (0.4528); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Leu78Pro (c.233T>C)?

CDKN2A p.Leu78Pro (c.233T>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.Leu78Pro (c.233T>C) in the general population?

CDKN2A p.Leu78Pro (c.233T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDKN2A p.Leu78Pro (c.233T>C)?

AlphaMissense predicts ambiguous (score 0.4528) — an in-silico prediction, not a clinical call.

CDKN2A p.Leu78Pro

c.233T>C · rs1554654118 · VCV483349

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4528 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,603,290)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4528	ambiguous
REVEL	0.73	pathogenic-leaning
SaProt	LLR -10.99	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.8	GERP 2, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	23.3	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

No allele count reported in gnomAD v4.1 (AN 1,603,290). 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.Leu78Pro
Coding: c.233T>C
MANE Select: NM_000077
dbSNP: rs1554654118
Type: single nucleotide variant
Location: chr9:21971126 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 78: 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

Similar variants

CDKN2A p.Leu78Phe Uncertain significance ★★ ⚠ same residue
CDKN2A p.Leu78Val Uncertain significance ★★ ⚠ same residue
CDKN2A p.Leu78= Conflicting classifications of pathogenicity ★ same residue
CDKN2A p.Leu78Arg Uncertain significance ★ ⚠ same residue
CDKN2A c.150+2T>G Likely pathogenic ★★ same condition
CDKN2A c.151-1G>C Pathogenic ★★ same condition
CDKN2A c.151-1G>T Pathogenic/Likely pathogenic ★★ same condition
CDKN2A c.151-2A>G Pathogenic/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-leu78pro (accessed [today's date]).

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