Is CDKN2D p.Leu143Val (c.427T>G) pathogenic?

CDKN2D p.Leu143Val (c.427T>G) is classified Uncertain significance in CDKN2D (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-07). AlphaMissense: likely benign (0.126); Very rare (popmax 8.47e-05%, nfe).

How common is CDKN2D p.Leu143Val (c.427T>G) in the general population?

CDKN2D p.Leu143Val (c.427T>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CDKN2D p.Leu143Val (c.427T>G)?

AlphaMissense predicts likely benign (score 0.126) — an in-silico prediction, not a clinical call.

CDKN2D p.Leu143Val

c.427T>G · rs1256898998 · VCV3141672

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.126 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.126	likely benign
REVEL	0.274	benign-leaning
SaProt	LLR -9.57	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP -2, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 1,592 bp · p 0.022 · regional, not allelic
Overall
CADD	13.63	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 8.47e-05% European (non-Finnish) · 1/1,179,970 alleles

Overall 0.000657% 1/152,174 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: CDKN2D
Protein: p.Leu143Val
Coding: c.427T>G
MANE Select: NM_001800
dbSNP: rs1256898998
Type: single nucleotide variant
Location: chr19:10567132 (GRCh38)
Gene constraint: LOEUF 1.426 · pLI 0.24 (gnomAD)
Structure: AlphaFold pLDDT 95.91 · 2 PDB
Residue 143: 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.Ala146Thr 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

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-leu143val (accessed [today's date]).

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