Is CDH15 p.Arg581Ser (c.1741C>A) pathogenic?

CDH15 p.Arg581Ser (c.1741C>A) is classified Uncertain significance in CDH15 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-19). AlphaMissense: likely benign (0.1527); Rare (popmax 0.804%, eas); Associated with intellectual disability, autosomal dominant 3.

What condition is associated with CDH15 p.Arg581Ser (c.1741C>A)?

CDH15 p.Arg581Ser (c.1741C>A) is associated with intellectual disability, autosomal dominant 3 (ClinVar).

How common is CDH15 p.Arg581Ser (c.1741C>A) in the general population?

CDH15 p.Arg581Ser (c.1741C>A) is rare (popmax 0.804%, eas) (gnomAD).

What do computational predictors say about CDH15 p.Arg581Ser (c.1741C>A)?

AlphaMissense predicts likely benign (score 0.1527) — an in-silico prediction, not a clinical call.

CDH15 p.Arg581Ser

c.1741C>A · VCV3581409

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1527 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.804%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability, autosomal dominant 3

Computational evidence

Protein change
AlphaMissense	0.1527	likely benign
REVEL	0.19	benign-leaning
SaProt	LLR -6.60	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.3	GERP -3.7, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 23 kb · p 5e-10 · regional, not allelic
Overall
CADD	18.75	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.804% East Asian · 330/41,056 alleles

Filtering AF 0.732% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.704%

Overall 0.0217% 334/1,535,930 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.804%	124
Finnishnot grpmax-eligible	0.0045%	22,219
Remaining individualsnot grpmax-eligible	0.00334%	29,922

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.Arg581Ser
Coding: c.1741C>A
MANE Select: NM_004933
Type: single nucleotide variant
Location: chr16:89192330 (GRCh38)
Gene constraint: LOEUF 1.41 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 78.70
Residue 581: the cadherin 5 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.Arg581His 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-arg581ser (accessed [today's date]).

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