Is CDKN2A p.Asp146His (c.436G>C) pathogenic?

CDKN2A p.Asp146His (c.436G>C) is classified Uncertain significance in CDKN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-27). AlphaMissense: likely benign (0.1334); Very rare (popmax 8.47e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Asp146His (c.436G>C)?

CDKN2A p.Asp146His (c.436G>C) is associated with hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.Asp146His (c.436G>C) in the general population?

CDKN2A p.Asp146His (c.436G>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CDKN2A p.Asp146His (c.436G>C)?

AlphaMissense predicts likely benign (score 0.1334) — an in-silico prediction, not a clinical call.

CDKN2A p.Asp146His

c.436G>C · rs1563888589 · VCV824834

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1334 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1334	likely benign
REVEL	0.33	indeterminate
SaProt	LLR -6.93	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.36	GERP -1.9
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	11.88	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,036 alleles

Overall 6.85e-05% 1/1,460,116 alleles · very rare

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.Asp146His
Coding: c.436G>C
MANE Select: NM_000077
dbSNP: rs1563888589
Type: single nucleotide variant
Location: chr9:21970923 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 146: a β-strand

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.Asp146Gly Uncertain significance ★★ ⚠ same residue
CDKN2A p.Asp146Val Uncertain significance ★★ ⚠ same residue
CDKN2A p.Asp146Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A p.Asp146= Likely benign ★ same residue
CDKN2A p.Asp146Glu Uncertain significance ★ ⚠ same residue
CDKN2A p.Asp146Tyr Uncertain significance ★ ⚠ same residue
CDKN2A c.150+2T>G Likely 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-asp146his (accessed [today's date]).

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