Is CDKN2D p.Ala146Thr (c.436G>A) pathogenic?

CDKN2D p.Ala146Thr (c.436G>A) is classified Uncertain significance in CDKN2D (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-27). AlphaMissense: likely pathogenic (0.7591); Absent from gnomAD v4.1.

How common is CDKN2D p.Ala146Thr (c.436G>A) in the general population?

CDKN2D p.Ala146Thr (c.436G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDKN2D p.Ala146Thr (c.436G>A)?

AlphaMissense predicts likely pathogenic (score 0.7591) — an in-silico prediction, not a clinical call.

CDKN2D p.Ala146Thr

c.436G>A · rs1216315244 · VCV2257651

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7591 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7591	likely pathogenic
REVEL	0.721	pathogenic-leaning
SaProt	LLR -13.59	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.1, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 1,592 bp · p 0.022 · regional, not allelic
Overall
CADD	24.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CDKN2D
Protein: p.Ala146Thr
Coding: c.436G>A
MANE Select: NM_001800
dbSNP: rs1216315244
Type: single nucleotide variant
Location: chr19:10567123 (GRCh38)
Gene constraint: LOEUF 1.426 · pLI 0.24 (gnomAD)
Structure: AlphaFold pLDDT 95.91 · 2 PDB
Residue 146: an α-helix

Full CDKN2D gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDKN2D p.Ala128Pro Uncertain significance ★ ⚠ same type
CDKN2D p.Ala137Pro Uncertain significance ★ ⚠ same type
CDKN2D p.Ala57Thr Uncertain significance ★ ⚠ same type
CDKN2D p.Arg7Pro Uncertain significance ★ ⚠ same type
CDKN2D p.Arg83Cys Uncertain significance ★ same type
CDKN2D p.Asp20Asn Uncertain significance ★ ⚠ same type
CDKN2D p.Gln152Pro Uncertain significance ★ ⚠ same type
CDKN2D p.Glu23Gln 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/cdkn2d-p-ala146thr (accessed [today's date]).

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