Is CDH15 p.Arg190Trp (c.568C>T) pathogenic?

CDH15 p.Arg190Trp (c.568C>T) is classified Conflicting classifications of pathogenicity in CDH15 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-05-26). AlphaMissense: likely benign (0.1545); Ultra-rare (popmax 0.0165%, mid); Associated with intellectual disability, autosomal dominant 3.

What condition is associated with CDH15 p.Arg190Trp (c.568C>T)?

CDH15 p.Arg190Trp (c.568C>T) is associated with intellectual disability, autosomal dominant 3 (ClinVar).

How common is CDH15 p.Arg190Trp (c.568C>T) in the general population?

CDH15 p.Arg190Trp (c.568C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CDH15 p.Arg190Trp (c.568C>T)?

AlphaMissense predicts likely benign (score 0.1545) — an in-silico prediction, not a clinical call.

CDH15 p.Arg190Trp

c.568C>T · rs137923863 · VCV803282

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1545 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability, autosomal dominant 3

Computational evidence

Protein change
AlphaMissense	0.1545	likely benign
REVEL	0.224	benign-leaning
SaProt	LLR -14.04	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 1.5	GERP 1.4, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 23 kb · p 5e-10 · regional, not allelic
Overall
CADD	24.9	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 0.0165% Middle Eastern · 1/6,076 alleles

Filtering AF 0.00316% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00279%

Overall 0.00361% 58/1,605,514 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,076
Ashkenazi Jewishnot grpmax-eligible	0.0136%	7,345
Admixed American	0.00505%	19,791
European (non-Finnish)	0.00408%	24,511
Remaining individualsnot grpmax-eligible	0.00161%	62,112
South Asian	0.00112%	89,606

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.Arg190Trp
Coding: c.568C>T
MANE Select: NM_004933
dbSNP: rs137923863
Type: single nucleotide variant
Location: chr16:89185238 (GRCh38)
Gene constraint: LOEUF 1.41 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 78.70
Residue 190: the cadherin 2 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.Arg190Gln Uncertain significance ★ ⚠ same residue
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

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-arg190trp (accessed [today's date]).

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