Is CDH15 p.Arg556Cys (c.1666C>T) pathogenic?

CDH15 p.Arg556Cys (c.1666C>T) is classified Benign in CDH15 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-01). AlphaMissense: likely benign (0.2631); Ultra-rare (popmax 0.0354%, amr).

How common is CDH15 p.Arg556Cys (c.1666C>T) in the general population?

CDH15 p.Arg556Cys (c.1666C>T) is ultra-rare (popmax 0.0354%, amr) (gnomAD).

What do computational predictors say about CDH15 p.Arg556Cys (c.1666C>T)?

AlphaMissense predicts likely benign (score 0.2631) — an in-silico prediction, not a clinical call.

CDH15 p.Arg556Cys

c.1666C>T · rs750253626 · VCV2647035

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2631 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0354%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2631	likely benign
REVEL	0.219	benign-leaning
SaProt	LLR -10.01	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 1.2	GERP -0.051, phastCons 0.73
Regional constraint	o/e 1.18	unconstrained · MANE · 23 kb · p 5e-10 · regional, not allelic
Overall
CADD	24.4	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 0.0354% Admixed American · 18/50,796 alleles

Filtering AF 0.0229% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0189%

Overall 0.0295% 452/1,530,182 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.04%	96
Remaining individualsnot grpmax-eligible	0.099%	1,010
Admixed Americangrpmax	0.0354%	2,822
European (non-Finnish)	0.00664%	15,067
African / African-American	0.00276%	36,230

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg556Cys
Coding: c.1666C>T
MANE Select: NM_004933
dbSNP: rs750253626
Type: single nucleotide variant
Location: chr16:89192255 (GRCh38)
Gene constraint: LOEUF 1.41 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 78.70
Residue 556: the cadherin 5 domain

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

Similar variants

CDH3 p.Cys556= Uncertain significance ★ same residue
CDH3 p.Cys556Gly Uncertain significance ★ ⚠ 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-arg556cys (accessed [today's date]).

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