Is CDKN2A p.Ala68Val (c.203C>T) pathogenic?

CDKN2A p.Ala68Val (c.203C>T) is classified Conflicting classifications of pathogenicity in CDKN2A (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-10-14). AlphaMissense: likely pathogenic (0.676); Very rare (popmax 8.5e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Ala68Val (c.203C>T)?

CDKN2A p.Ala68Val (c.203C>T) is associated with hereditary neoplastic syndrome, melanoma and neural system tumor syndrome, melanoma-pancreatic cancer syndrome (ClinVar).

How common is CDKN2A p.Ala68Val (c.203C>T) in the general population?

CDKN2A p.Ala68Val (c.203C>T) is very rare (popmax 8.5e-05%, nfe) (gnomAD).

What do computational predictors say about CDKN2A p.Ala68Val (c.203C>T)?

AlphaMissense predicts likely pathogenic (score 0.676) — an in-silico prediction, not a clinical call.

CDKN2A p.Ala68Val

c.203C>T · rs1060501260 · VCV406701

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.676 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.5e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.676	likely pathogenic
REVEL	0.874	moderately pathogenic-leaning
SaProt	LLR -10.90	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 9.7	GERP 2.1, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	24.9	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

Grpmax group 8.5e-05% European (non-Finnish) · 1/1,176,910 alleles

Overall 6.94e-05% 1/1,441,598 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.Ala68Val
Coding: c.203C>T
MANE Select: NM_000077
dbSNP: rs1060501260
Type: single nucleotide variant
Location: chr9:21971156 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 68: a UniProt-annotated variant site (in melanoma; loss of cdk4 binding); a UniProt-annotated variant site (in cmm2; requires 2 nucleotide substitutions); a UniProt-annotated variant site (in an esophagus tumor); a UniProt-annotated variant site (in); 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

Also linked: melanoma and neural system tumor syndrome melanoma-pancreatic cancer syndrome familial melanoma

Similar variants

CDKN2A p.Ala68Gly Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ala68Ser Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ala68Thr Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ala68Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A p.Ala68= Likely benign ★ same residue
CDKN2A p.Ala68Leu Likely pathogenic ★★ same residue
CDKN2A p.Ala68Ter Pathogenic ★ same residue
CDKN2A c.150+1G>A 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-ala68val (accessed [today's date]).

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