Is CDH15 p.Leu422Pro (c.1265T>C) pathogenic?

CDH15 p.Leu422Pro (c.1265T>C) is classified Uncertain significance in CDH15 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-02). AlphaMissense: likely pathogenic (0.9823); Absent from gnomAD v4.1; Associated with intellectual disability, autosomal dominant 3.

What condition is associated with CDH15 p.Leu422Pro (c.1265T>C)?

CDH15 p.Leu422Pro (c.1265T>C) is associated with intellectual disability, autosomal dominant 3 (ClinVar).

How common is CDH15 p.Leu422Pro (c.1265T>C) in the general population?

CDH15 p.Leu422Pro (c.1265T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDH15 p.Leu422Pro (c.1265T>C)?

AlphaMissense predicts likely pathogenic (score 0.9823) — an in-silico prediction, not a clinical call.

CDH15 p.Leu422Pro

c.1265T>C · VCV4851407

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9823 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability, autosomal dominant 3

Computational evidence

Protein change
AlphaMissense	0.9823	likely pathogenic · top 3% in CDH15
REVEL	0.676	pathogenic-leaning
SaProt	LLR -17.52	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 7.7	GERP 1.5, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 23 kb · p 5e-10 · regional, not allelic
Overall
CADD	29.2	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: CDH15
Protein: p.Leu422Pro
Coding: c.1265T>C
MANE Select: NM_004933
Type: single nucleotide variant
Location: chr16:89191362 (GRCh38)
Gene constraint: LOEUF 1.41 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 78.70
Residue 422: the cadherin 4 domain

Full CDH15 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual disability, autosomal dominant 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CDH15 p.Arg92Trp Uncertain significance ★★ ⚠ same condition
CDH15 p.Gly514Arg Uncertain significance ★★ ⚠ same condition
CDH15 p.Pro347Leu Uncertain significance ★★ ⚠ same condition
CDH15 p.Pro347Ser Uncertain significance ★★ ⚠ same condition
CDH15 p.Thr158Ala Uncertain significance ★★ ⚠ same condition
CDH15 p.Val43Leu Uncertain significance ★★ ⚠ same condition
CDH15 p.Ala122Val Likely benign ★★ ⚠ same condition
CDH15 p.Arg60Cys Likely benign ★★ ⚠ same condition

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/cdh15-p-leu422pro (accessed [today's date]).

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