Is CDKN2A p.Asp125His (c.373G>C) pathogenic?

CDKN2A p.Asp125His (c.373G>C) is classified Conflicting classifications of pathogenicity in CDKN2A (ClinVar, Conflicting submitters, 15 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.3071); Ultra-rare (popmax 0.0463%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Asp125His (c.373G>C)?

CDKN2A p.Asp125His (c.373G>C) is associated with hereditary neoplastic syndrome, melanoma, cutaneous malignant, susceptibility to, 2, melanoma and neural system tumor syndrome (ClinVar).

How common is CDKN2A p.Asp125His (c.373G>C) in the general population?

CDKN2A p.Asp125His (c.373G>C) is ultra-rare (popmax 0.0463%, nfe) (gnomAD).

What do computational predictors say about CDKN2A p.Asp125His (c.373G>C)?

AlphaMissense predicts likely benign (score 0.3071) — an in-silico prediction, not a clinical call.

CDKN2A p.Asp125His

c.373G>C · rs146179135 · VCV41577

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 15 submitters

AlphaMissense

likely benign

0.3071 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0463%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.3071	likely benign
REVEL	0.366	indeterminate
SaProt	LLR -8.24	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.67	GERP -2.5
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	9.953	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 0.0463% European (non-Finnish) · 546/1,180,002 alleles

Filtering AF 0.043% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0417%

Overall 0.0353% 569/1,610,420 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0463%	2,161
Remaining individualsnot grpmax-eligible	0.0224%	4,458
African / African-American	0.012%	8,339

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.Asp125His
Coding: c.373G>C
MANE Select: NM_000077
dbSNP: rs146179135
Type: single nucleotide variant
Location: chr9:21970986 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 125: an α-helix; 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, cutaneous malignant, susceptibility to, 2 melanoma and neural system tumor syndrome melanoma-pancreatic cancer syndrome familial melanoma

Similar variants

CDKN2A p.Asp125Asn Uncertain significance ★★ ⚠ same residue
CDKN2A p.Asp125Glu Uncertain significance ★★ ⚠ same residue
CDKN2A p.Asp125Gly 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
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-asp125his (accessed [today's date]).

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