Is CDKN2A p.Leu94Pro (c.281T>C) pathogenic?

CDKN2A p.Leu94Pro (c.281T>C) is classified Likely pathogenic in CDKN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2019-04-16). AlphaMissense: likely pathogenic (0.9693); Absent from gnomAD v4.1.

How common is CDKN2A p.Leu94Pro (c.281T>C) in the general population?

CDKN2A p.Leu94Pro (c.281T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDKN2A p.Leu94Pro (c.281T>C)?

AlphaMissense predicts likely pathogenic (score 0.9693) — an in-silico prediction, not a clinical call.

CDKN2A p.Leu94Pro

c.281T>C · rs1819703656 · VCV1215320

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9693 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9693	likely pathogenic ✓ concordant with ClinVar · top 3% in CDKN2A
REVEL	0.623	indeterminate
SaProt	LLR -14.31	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	25.4	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

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.Leu94Pro
Coding: c.281T>C
MANE Select: NM_000077
dbSNP: rs1819703656
Type: single nucleotide variant
Location: chr9:21971078 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 94: an α-helix; a UniProt-annotated variant site (in cmm2); the 'disordered' region

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

Similar variants

CDKN2A p.Leu94Val Uncertain significance ★★ ⚠ same residue
CDKN2A p.Leu94Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A p.Leu94= Likely benign ★ same residue
CDKN2A c.150+1G>A Likely pathogenic ★★ same type
CDKN2A c.150+2T>G Likely pathogenic ★★ same type
CDKN2A c.151-1G>A Pathogenic ★★ same type
CDKN2A c.151-1G>C Pathogenic ★★ same type
CDKN2A c.151-1G>T Pathogenic/Likely pathogenic ★★ same type

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-leu94pro (accessed [today's date]).

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