Is CDH15 p.Pro347Leu (c.1040C>T) pathogenic?

CDH15 p.Pro347Leu (c.1040C>T) is classified Uncertain significance in CDH15 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-23). AlphaMissense: likely benign (0.0974); Ultra-rare (popmax 0.0164%, mid); Associated with intellectual disability, autosomal dominant 3.

What condition is associated with CDH15 p.Pro347Leu (c.1040C>T)?

CDH15 p.Pro347Leu (c.1040C>T) is associated with intellectual disability, autosomal dominant 3 (ClinVar).

How common is CDH15 p.Pro347Leu (c.1040C>T) in the general population?

CDH15 p.Pro347Leu (c.1040C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about CDH15 p.Pro347Leu (c.1040C>T)?

AlphaMissense predicts likely benign (score 0.0974) — an in-silico prediction, not a clinical call.

CDH15 p.Pro347Leu

c.1040C>T · rs769615158 · VCV2647030

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0974 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability, autosomal dominant 3

Computational evidence

Protein change
AlphaMissense	0.0974	likely benign
REVEL	0.224	benign-leaning
SaProt	LLR -12.26	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.4, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 23 kb · p 5e-10 · regional, not allelic
Overall
CADD	24.1	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00299% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00267%

Overall 0.0036% 58/1,612,372 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.00801%	12,482
Finnishnot grpmax-eligible	0.00636%	15,719
European (non-Finnish)	0.0039%	25,648
African / African-American	0.00133%	74,938
South Asian	0.0011%	90,948

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: CDH15
Protein: p.Pro347Leu
Coding: c.1040C>T
MANE Select: NM_004933
dbSNP: rs769615158
Type: single nucleotide variant
Location: chr16:89190304 (GRCh38)
Gene constraint: LOEUF 1.41 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 78.70
Residue 347: the cadherin 3 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.Pro347Ser Uncertain significance ★★ ⚠ same residue
CDH3 p.Gln347His Uncertain significance ★ ⚠ same residue
CDH15 p.Arg92Trp Uncertain significance ★★ ⚠ same condition
CDH15 p.Gly514Arg 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-pro347leu (accessed [today's date]).

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