Is CDH15 p.Ser535Arg (c.1605C>A) pathogenic?

CDH15 p.Ser535Arg (c.1605C>A) is classified Uncertain significance in CDH15 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-14). AlphaMissense: likely benign (0.2457); Very rare (popmax 0.00214%, nfe).

How common is CDH15 p.Ser535Arg (c.1605C>A) in the general population?

CDH15 p.Ser535Arg (c.1605C>A) is very rare (popmax 0.00214%, nfe) (gnomAD).

What do computational predictors say about CDH15 p.Ser535Arg (c.1605C>A)?

AlphaMissense predicts likely benign (score 0.2457) — an in-silico prediction, not a clinical call.

CDH15 p.Ser535Arg

c.1605C>A · VCV3998830

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2457 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00214%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2457	likely benign
REVEL	0.301	indeterminate
SaProt	LLR -5.33	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.76 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.7	GERP 1.2, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 23 kb · p 5e-10 · regional, not allelic
Overall
CADD	20.4	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 0.00214% European (non-Finnish) · 25/1,169,586 alleles

Filtering AF 0.00147% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00124%

Overall 0.00171% 27/1,579,642 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00214%	46,783
Remaining individualsnot grpmax-eligible	0.00163%	61,404
African / African-American	0.00134%	74,586

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.Ser535Arg
Coding: c.1605C>A
MANE Select: NM_004933
Type: single nucleotide variant
Location: chr16:89191884 (GRCh38)
Gene constraint: LOEUF 1.41 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 78.70
Residue 535: the cadherin 5 domain

Full CDH15 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDH15 p.Ser535Gly Uncertain significance ★ ⚠ same residue
CDH3 p.Leu535= Likely benign ★ same residue
CDH3 c.1796-2A>G Pathogenic ★★ same type
CDH3 c.691+1G>A Pathogenic/Likely pathogenic ★★ same type
CDH3 p.Arg103Ter Pathogenic ★★ same type
CDH3 p.Arg221Ter Pathogenic ★★ same type
CDH3 p.Arg503His Pathogenic/Likely pathogenic ★★ ⚠ same type
CDH3 p.Gln299Ter Pathogenic ★★ same type

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-ser535arg (accessed [today's date]).

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