Is CDKN2AIP p.Phe457Cys (c.1370T>G) pathogenic?

CDKN2AIP p.Phe457Cys (c.1370T>G) is classified Uncertain significance in CDKN2AIP (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-11). AlphaMissense: likely pathogenic (0.9937); Very rare (popmax 0.000169%, nfe).

How common is CDKN2AIP p.Phe457Cys (c.1370T>G) in the general population?

CDKN2AIP p.Phe457Cys (c.1370T>G) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about CDKN2AIP p.Phe457Cys (c.1370T>G)?

AlphaMissense predicts likely pathogenic (score 0.9937) — an in-silico prediction, not a clinical call.

CDKN2AIP p.Phe457Cys

c.1370T>G · rs2476985085 · VCV2610241

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9937 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9937	likely pathogenic · top 5% in CDKN2AIP
REVEL	0.281	benign-leaning
SaProt	LLR -8.93	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 442 bp · p 7.7e-05 · regional, not allelic
Overall
CADD	27.6	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 0.000169% European (non-Finnish) · 2/1,179,972 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,758 alleles · very rare

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: CDKN2AIP
Protein: p.Phe457Cys
Coding: c.1370T>G
MANE Select: NM_017632
dbSNP: rs2476985085
Type: single nucleotide variant
Location: chr4:183447054 (GRCh38)
Gene constraint: LOEUF 0.49 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 63.54

Full CDKN2AIP gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDKN2AIP p.Ala104Ser Uncertain significance ★ ⚠ same type
CDKN2AIP p.Ala163Thr Uncertain significance ★ ⚠ same type
CDKN2AIP p.Ala281Pro Uncertain significance ★ ⚠ same type
CDKN2AIP p.Ala315Ser Uncertain significance ★ ⚠ same type
CDKN2AIP p.Ala327Gly Uncertain significance ★ ⚠ same type
CDKN2AIP p.Ala367Val Uncertain significance ★ ⚠ same type
CDKN2AIP p.Ala47Val Uncertain significance ★ ⚠ same type
CDKN2AIP p.Ala53Val Uncertain significance ★ ⚠ same type

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/cdkn2aip-p-phe457cys (accessed [today's date]).

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