Is CDKN2A p.Pro3Thr (c.7C>A) pathogenic?

CDKN2A p.Pro3Thr (c.7C>A) is classified Uncertain significance in CDKN2A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-13). AlphaMissense: likely benign (0.0566); Very rare (popmax 0.00111%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with CDKN2A p.Pro3Thr (c.7C>A)?

CDKN2A p.Pro3Thr (c.7C>A) is associated with hereditary neoplastic syndrome (ClinVar).

How common is CDKN2A p.Pro3Thr (c.7C>A) in the general population?

CDKN2A p.Pro3Thr (c.7C>A) is very rare (popmax 0.00111%, sas) (gnomAD).

What do computational predictors say about CDKN2A p.Pro3Thr (c.7C>A)?

AlphaMissense predicts likely benign (score 0.0566) — an in-silico prediction, not a clinical call.

CDKN2A p.Pro3Thr

c.7C>A · VCV3489667

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0566 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00111%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0566	likely benign
REVEL	0.374	indeterminate
SaProt	LLR -7.31	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 0.25	GERP -3.4, phastCons 0.001
Regional constraint	o/e 1.13	unconstrained · MANE · 6,595 bp · p 0.04 · regional, not allelic
Overall
CADD	13.75	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00111% South Asian · 1/89,990 alleles

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

Overall 0.000278% 4/1,439,508 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00111%	89,990
European (non-Finnish)	0.000256%	391,166

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.Pro3Thr
Coding: c.7C>A
MANE Select: NM_000077
Type: single nucleotide variant
Location: chr9:21974821 (GRCh38)
Gene constraint: LOEUF 0.791 · pLI 0.62 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.02 · 5 PDB
Residue 3: the 'interaction with cdk5rap3 and mdm2' 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

Similar variants

CDKN2A p.Arg3Cys Uncertain significance ★★ same residue
CDKN2A p.Arg3His Uncertain significance ★★ same residue
CDKN2A p.Pro3Ala Uncertain significance ★★ ⚠ same residue
CDKN2A p.Arg3= Benign/Likely benign ★★ same residue
CDKN2A p.Pro3= Benign/Likely benign ★★ same residue
CDKN2A p.Arg3Leu Uncertain significance ★ same residue
CDKN2A p.Pro3Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CDKN2A c.150+2T>G 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-pro3thr (accessed [today's date]).

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