Is CDKN2A p.Ala100Ser (c.298G>T) pathogenic?

CDKN2A p.Ala100Ser (c.298G>T) is classified Conflicting classifications of pathogenicity in CDKN2A (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.1502); Rare (popmax 0.117%, afr); Associated with familial melanoma.

What condition is associated with CDKN2A p.Ala100Ser (c.298G>T)?

CDKN2A p.Ala100Ser (c.298G>T) is associated with familial melanoma, melanoma-pancreatic cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.Ala100Ser (c.298G>T) in the general population?

CDKN2A p.Ala100Ser (c.298G>T) is rare (popmax 0.117%, afr) (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.Ala100Ser (c.298G>T)?

AlphaMissense predicts likely benign (score 0.1502) — an in-silico prediction, not a clinical call.

CDKN2A p.Ala100Ser

c.298G>T · rs200863613 · VCV127524

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1502 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.117%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial melanoma

Computational evidence

Protein change
AlphaMissense	0.1502	likely benign
REVEL	0.263	benign-leaning
SaProt	LLR -8.79	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 2, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	17.98	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 0.117% African / African-American · 88/75,008 alleles

Filtering AF 0.0975% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0901%

Overall 0.0061% 98/1,605,346 alleles · rare exomes 45/1,453,014 · genomes 53/152,332 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.117%	852
Remaining individualsnot grpmax-eligible	0.0112%	8,902
Admixed American	0.00167%	59,946
European (non-Finnish)	0.00017%	589,713

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.Ala100Ser
Coding: c.298G>T
MANE Select: NM_000077
dbSNP: rs200863613
Type: single nucleotide variant
Location: chr9:21971061 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 100: an α-helix; a UniProt-annotated variant site (in cmm2; requires 2 nucleotide substitutions); 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-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.Ala100Thr Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ala100Val Uncertain significance ★★ ⚠ same residue
CDKN2A p.Ala100= Conflicting classifications of pathogenicity ★ 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
CDKN2A c.151-1G>C Pathogenic ★★ same condition
CDKN2A c.151-1G>T Pathogenic/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-ala100ser (accessed [today's date]).

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