Is CDH15 p.Trp34fs (c.100del) pathogenic?

CDH15 p.Trp34fs (c.100del) is classified Uncertain significance in CDH15 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-01). Rare (popmax 0.193%, amr); Associated with intellectual disability, autosomal dominant 3.

What condition is associated with CDH15 p.Trp34fs (c.100del)?

CDH15 p.Trp34fs (c.100del) is associated with intellectual disability, autosomal dominant 3 (ClinVar).

How common is CDH15 p.Trp34fs (c.100del) in the general population?

CDH15 p.Trp34fs (c.100del) is rare (popmax 0.193%, amr) (gnomAD).

CDH15 p.Trp34fs

c.100del · rs770141326 · VCV1686550

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

rare (popmax 0.193%, amr)

Conditions

intellectual disability, autosomal dominant 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 14
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.28	GERP -2.5, phastCons 0.97
Overall
CADD	29.6	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.193% Admixed American · 116/60,004 alleles

Filtering AF 0.165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.154%

Overall 0.00738% 119/1,613,458 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.193%	517
South Asian	0.0022%	45,546
African / African-American	0.00133%	74,940

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.Trp34fs
Coding: c.100del
MANE Select: NM_004933
dbSNP: rs770141326
Type: Deletion
Location: chr16:89179473 (GRCh38)
Gene constraint: LOEUF 1.41 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 78.70

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.Tyr739del Uncertain significance ★★ same condition
CDH3 p.Ala34Thr Uncertain significance ★★ ⚠ same residue
CDH15 p.Gln699fs Uncertain significance ★ same condition
CDH3 p.Ala34Val Uncertain significance ★ ⚠ same residue
CDH15 p.Tyr667_Asp668del Likely benign ★ same condition
CDH3 p.Ala34= Likely benign ★ same residue
CDH15 p.Arg92Trp Uncertain significance ★★ ⚠ same condition
CDH15 p.Gly514Arg Uncertain significance ★★ ⚠ 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-trp34fs (accessed [today's date]).

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