Is CDKN2A p.Asn71Ser (c.212A>G) pathogenic?

CDKN2A p.Asn71Ser (c.212A>G) is classified Likely pathogenic in CDKN2A (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-19). AlphaMissense: likely benign (0.2129); Ultra-rare (popmax 0.0188%, mid); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Asn71Ser (c.212A>G)?

CDKN2A p.Asn71Ser (c.212A>G) is associated with hereditary neoplastic syndrome, familial melanoma (ClinVar).

How common is CDKN2A p.Asn71Ser (c.212A>G) in the general population?

CDKN2A p.Asn71Ser (c.212A>G) is ultra-rare (popmax 0.0188%, mid) (gnomAD).

What do computational predictors say about CDKN2A p.Asn71Ser (c.212A>G)?

AlphaMissense predicts likely benign (score 0.2129) — an in-silico prediction, not a clinical call.

CDKN2A p.Asn71Ser

c.212A>G · rs559848002 · VCV418121

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2129 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0188%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.2129	likely benign ⚠ discordant with ClinVar
REVEL	0.76	pathogenic-leaning
SaProt	LLR -8.76	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	24.5	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 0.0188% Middle Eastern · 1/5,328 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000376% 6/1,593,656 alleles · ultra-rare exomes 5/1,441,448 · genomes 1/152,208 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0188%	5,328
Admixed American	0.00169%	59,174
Remaining individualsnot grpmax-eligible	0.00162%	61,912
European (non-Finnish)	0.000255%	392,221

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.Asn71Ser
Coding: c.212A>G
MANE Select: NM_000077
dbSNP: rs559848002
Type: single nucleotide variant
Location: chr9:21971147 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 71: a UniProt-annotated variant site (in melanoma; loss of cdk4 binding); a UniProt-annotated variant site (in cmm2); 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: familial melanoma

Similar variants

CDKN2A p.Asn71Lys Likely pathogenic ★★ same residue
CDKN2A p.Asn71= Likely benign ★★ same residue
CDKN2A p.Asn71Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A p.Asn71Tyr Uncertain significance ★ ⚠ same residue
CDKN2A p.Asn71fs Pathogenic/Likely pathogenic ★★ 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-asn71ser (accessed [today's date]).

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