Is CDKN2A p.His83Arg (c.248A>G) pathogenic?

CDKN2A p.His83Arg (c.248A>G) is classified Conflicting classifications of pathogenicity in CDKN2A (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-05-14). AlphaMissense: likely pathogenic (0.9431); Very rare (popmax 0.00223%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.His83Arg (c.248A>G)?

CDKN2A p.His83Arg (c.248A>G) is associated with hereditary neoplastic syndrome, melanoma-pancreatic cancer syndrome (ClinVar).

How common is CDKN2A p.His83Arg (c.248A>G) in the general population?

CDKN2A p.His83Arg (c.248A>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CDKN2A p.His83Arg (c.248A>G)?

AlphaMissense predicts likely pathogenic (score 0.9431) — an in-silico prediction, not a clinical call.

CDKN2A p.His83Arg

c.248A>G · rs1057519881 · VCV376379

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9431 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9431	likely pathogenic · top 6% in CDKN2A
REVEL	0.81	moderately pathogenic-leaning
SaProt	LLR -14.90	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 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	25.9	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 0.00223% East Asian · 1/44,850 alleles

Overall 6.23e-05% 1/1,604,494 alleles · very rare exomes 0/1,452,156 · genomes 1/152,338 · joint denominator

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.His83Arg
Coding: c.248A>G
MANE Select: NM_000077
dbSNP: rs1057519881
Type: single nucleotide variant
Location: chr9:21971111 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 83: an α-helix; a UniProt-annotated variant site (in a lung tumor); a UniProt-annotated variant site (in); a UniProt-annotated variant site (in a pancreas tumor; also found in head and neck tumor); 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-pancreatic cancer syndrome

Similar variants

CDKN2A p.His83= Conflicting classifications of pathogenicity ★ same residue
CDKN2A p.His83Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A p.His83Tyr 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-his83arg (accessed [today's date]).

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