Is CDKN2A p.Gly35Val (c.104G>T) pathogenic?

CDKN2A p.Gly35Val (c.104G>T) is classified Uncertain significance in CDKN2A (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-31). AlphaMissense: likely pathogenic (0.8532); Very rare (popmax 0.00167%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Gly35Val (c.104G>T)?

CDKN2A p.Gly35Val (c.104G>T) is associated with hereditary neoplastic syndrome, familial melanoma (ClinVar).

How common is CDKN2A p.Gly35Val (c.104G>T) in the general population?

CDKN2A p.Gly35Val (c.104G>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CDKN2A p.Gly35Val (c.104G>T)?

AlphaMissense predicts likely pathogenic (score 0.8532) — an in-silico prediction, not a clinical call.

CDKN2A p.Gly35Val

c.104G>T · rs746834149 · VCV406709

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8532 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.8532	likely pathogenic
REVEL	0.862	moderately pathogenic-leaning
SaProt	LLR -14.84	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 2, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	26.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00167% Admixed American · 1/60,022 alleles

Overall 6.85e-05% 1/1,460,806 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.Gly35Val
Coding: c.104G>T
MANE Select: NM_000077
dbSNP: rs746834149
Type: single nucleotide variant
Location: chr9:21974724 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 35: a UniProt-annotated variant site (in cmm2; also found in a biliary tract tumor and a patient with uveal melanoma; partial loss of cdk4 binding); a UniProt-annotated variant site (in cmm2); a UniProt-annotated variant site (in cmm2; loss of cdk4 binding); 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

Also linked: familial melanoma

Similar variants

CDKN2A p.Gly35Arg Uncertain significance ★★ ⚠ same residue
CDKN2A p.Gly35Glu Uncertain significance ★★ ⚠ same residue
CDKN2A p.Gly35= Likely benign ★★ same residue
CDKN2A p.Ala35Pro Uncertain significance ★ same residue
CDKN2A p.Ala35Ser Uncertain significance ★ same residue
CDKN2A p.Ala35Val Uncertain significance ★ same residue
CDKN2A p.Gly35Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A p.Ala35= Likely benign ★ same residue

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-gly35val (accessed [today's date]).

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