Is CDKN2A p.Ile49Val (c.145A>G) pathogenic?

CDKN2A p.Ile49Val (c.145A>G) is classified Uncertain significance in CDKN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-05). AlphaMissense: likely benign (0.3085); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Ile49Val (c.145A>G)?

CDKN2A p.Ile49Val (c.145A>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.Ile49Val (c.145A>G) in the general population?

CDKN2A p.Ile49Val (c.145A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDKN2A p.Ile49Val (c.145A>G)?

AlphaMissense predicts likely benign (score 0.3085) — an in-silico prediction, not a clinical call.

CDKN2A p.Ile49Val

c.145A>G · VCV3489680

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3085 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.3085	likely benign
REVEL	0.478	indeterminate
SaProt	LLR -7.98	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 1.8	GERP 0.8, phastCons 0.99
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	20.5	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

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.Ile49Val
Coding: c.145A>G
MANE Select: NM_000077
Type: single nucleotide variant
Location: chr9:21974683 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 49: an α-helix; a UniProt-annotated variant site (in a biliary tract tumor); a UniProt-annotated variant site (in); the 'interaction with cdk5rap3 and mdm2' 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.Ile49Ser Pathogenic/Likely pathogenic ★★ same residue
CDKN2A p.Ile49Met Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ile49= Benign/Likely benign ★★ same residue
CDKN2A p.Leu49= Benign/Likely benign ★★ same residue
CDKN2A p.Ile49Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A p.Leu49Val 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-ile49val (accessed [today's date]).

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