Is CDKN2AIP p.Ala104Ser (c.310G>T) pathogenic?

CDKN2AIP p.Ala104Ser (c.310G>T) is classified Uncertain significance in CDKN2AIP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-24). AlphaMissense: ambiguous (0.482); Very rare (popmax 8.5e-05%, nfe).

How common is CDKN2AIP p.Ala104Ser (c.310G>T) in the general population?

CDKN2AIP p.Ala104Ser (c.310G>T) is very rare (popmax 8.5e-05%, nfe) (gnomAD).

What do computational predictors say about CDKN2AIP p.Ala104Ser (c.310G>T)?

AlphaMissense predicts ambiguous (score 0.482) — an in-silico prediction, not a clinical call.

CDKN2AIP p.Ala104Ser

c.310G>T · VCV4224798

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.482 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.5e-05%, nfe)

Computational evidence

Protein change
AlphaMissense	0.482	ambiguous
REVEL	0.347	indeterminate
SaProt	LLR -3.92	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 2, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 2,183 bp · p 0.0012 · regional, not allelic
Overall
CADD	25.8	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 8.5e-05% European (non-Finnish) · 1/1,176,098 alleles

Overall 0.000137% 2/1,457,564 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,372
European (non-Finnish)grpmax	8.5e-05%	1,176,098

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.Ala104Ser
Coding: c.310G>T
MANE Select: NM_017632
Type: single nucleotide variant
Location: chr4:183445572 (GRCh38)
Gene constraint: LOEUF 0.49 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 63.54
Residue 104: the xrn2-binding (xtbd) domain

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

Similar variants

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
CDKN2AIP p.Ala55Pro 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-ala104ser (accessed [today's date]).

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