Is CDKN2A p.Ala85Thr (c.253G>A) pathogenic?

CDKN2A p.Ala85Thr (c.253G>A) is classified Uncertain significance in CDKN2A (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-04). AlphaMissense: likely pathogenic (0.6836); Very rare (popmax 0.00017%, nfe); Associated with familial melanoma.

What condition is associated with CDKN2A p.Ala85Thr (c.253G>A)?

CDKN2A p.Ala85Thr (c.253G>A) is associated with familial melanoma, melanoma, cutaneous malignant, susceptibility to, 2, melanoma and neural system tumor syndrome (ClinVar).

How common is CDKN2A p.Ala85Thr (c.253G>A) in the general population?

CDKN2A p.Ala85Thr (c.253G>A) is very rare (popmax 0.00017%, nfe) (gnomAD).

How is Familial melanoma inherited?

Typically Autosomal dominant, Multigenic/multifactorial (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CDKN2A p.Ala85Thr (c.253G>A)?

AlphaMissense predicts likely pathogenic (score 0.6836) — an in-silico prediction, not a clinical call.

CDKN2A p.Ala85Thr

c.253G>A · rs878853646 · VCV236983

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.6836 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial melanoma

Computational evidence

Protein change
AlphaMissense	0.6836	likely pathogenic
REVEL	0.834	moderately pathogenic-leaning
SaProt	LLR -9.54	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 2, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	27.9	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 0.00017% European (non-Finnish) · 2/1,179,570 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000207% 3/1,452,112 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0018%	55,488
European (non-Finnish)grpmax	0.00017%	589,786

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala85Thr
Coding: c.253G>A
MANE Select: NM_000077
dbSNP: rs878853646
Type: single nucleotide variant
Location: chr9:21971106 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 85: an α-helix; 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

familial melanoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: melanoma, cutaneous malignant, susceptibility to, 2 melanoma and neural system tumor syndrome melanoma-pancreatic cancer syndrome hereditary neoplastic syndrome

For Familial melanoma (Orphanet):

Inheritance: Autosomal dominant, Multigenic/multifactorial
Onset: Adult
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

CDKN2A p.Ala85Pro Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ala85Ser Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ala85Val Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ala85= Likely benign ★ same residue
CDKN2A p.Ala85Phe Uncertain significance ★★ same residue
CDKN2A c.150+1G>A Likely pathogenic ★★ same condition
CDKN2A c.150+2T>G Likely pathogenic ★★ same condition
CDKN2A c.151-1G>A 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-ala85thr (accessed [today's date]).

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