Is CDKN2AIP p.Leu101Phe (c.301C>T) pathogenic?

CDKN2AIP p.Leu101Phe (c.301C>T) is classified Uncertain significance in CDKN2AIP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-09). AlphaMissense: ambiguous (0.4068); Very rare (popmax 0.00167%, amr).

How common is CDKN2AIP p.Leu101Phe (c.301C>T) in the general population?

CDKN2AIP p.Leu101Phe (c.301C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CDKN2AIP p.Leu101Phe (c.301C>T)?

AlphaMissense predicts ambiguous (score 0.4068) — an in-silico prediction, not a clinical call.

CDKN2AIP p.Leu101Phe

c.301C>T · rs1434866477 · VCV2265055

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4068 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4068	ambiguous
REVEL	0.136	moderately benign-leaning
SaProt	LLR -7.58	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
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 1.14	unconstrained · MANE · 2,183 bp · p 0.0012 · regional, not allelic
Overall
CADD	25.3	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 0.00167% Admixed American · 1/59,912 alleles

Overall 0.000343% 5/1,458,254 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00321%	31,190
Admixed Americangrpmax	0.00167%	59,912
South Asian	0.0011%	91,006
European (non-Finnish)	8.5e-05%	1,176,862

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Leu101Phe
Coding: c.301C>T
MANE Select: NM_017632
dbSNP: rs1434866477
Type: single nucleotide variant
Location: chr4:183445563 (GRCh38)
Gene constraint: LOEUF 0.49 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 63.54
Residue 101: the xrn2-binding (xtbd) domain

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-leu101phe (accessed [today's date]).

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