Is CDH15 p.Ser203Cys (c.607A>T) pathogenic?

CDH15 p.Ser203Cys (c.607A>T) is classified Uncertain significance in CDH15 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-07-03). AlphaMissense: likely benign (0.2584); Very rare (popmax 8.5e-05%, nfe); Associated with intellectual disability, autosomal dominant 3.

What condition is associated with CDH15 p.Ser203Cys (c.607A>T)?

CDH15 p.Ser203Cys (c.607A>T) is associated with intellectual disability, autosomal dominant 3 (ClinVar).

How common is CDH15 p.Ser203Cys (c.607A>T) in the general population?

CDH15 p.Ser203Cys (c.607A>T) is very rare (popmax 8.5e-05%, nfe) (gnomAD).

What do computational predictors say about CDH15 p.Ser203Cys (c.607A>T)?

AlphaMissense predicts likely benign (score 0.2584) — an in-silico prediction, not a clinical call.

CDH15 p.Ser203Cys

c.607A>T · rs1725146797 · VCV1098632

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2584 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.5e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

intellectual disability, autosomal dominant 3

Computational evidence

Protein change
AlphaMissense	0.2584	likely benign
REVEL	0.31	indeterminate
SaProt	LLR -10.90	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.1	GERP 0.36, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 23 kb · p 5e-10 · regional, not allelic
Overall
CADD	25.0	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 8.5e-05% European (non-Finnish) · 1/1,176,622 alleles

Overall 6.88e-05% 1/1,453,888 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: CDH15
Protein: p.Ser203Cys
Coding: c.607A>T
MANE Select: NM_004933
dbSNP: rs1725146797
Type: single nucleotide variant
Location: chr16:89185277 (GRCh38)
Gene constraint: LOEUF 1.41 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 78.70
Residue 203: 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.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-ser203cys (accessed [today's date]).

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