Is CDH15 p.Arg60Cys (c.178C>T) pathogenic?

CDH15 p.Arg60Cys (c.178C>T) is classified Likely benign in CDH15 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-01-19). AlphaMissense: likely benign (0.2629); Very rare (popmax 0.00505%, amr); Associated with intellectual disability, autosomal dominant 3.

What condition is associated with CDH15 p.Arg60Cys (c.178C>T)?

CDH15 p.Arg60Cys (c.178C>T) is associated with intellectual disability, autosomal dominant 3 (ClinVar).

How common is CDH15 p.Arg60Cys (c.178C>T) in the general population?

CDH15 p.Arg60Cys (c.178C>T) is very rare (popmax 0.00505%, amr) (gnomAD).

What do computational predictors say about CDH15 p.Arg60Cys (c.178C>T)?

AlphaMissense predicts likely benign (score 0.2629) — an in-silico prediction, not a clinical call.

CDH15 p.Arg60Cys

c.178C>T · rs121434539 · VCV17642

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2629 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00505%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

intellectual disability, autosomal dominant 3

Computational evidence

Protein change
AlphaMissense	0.2629	likely benign
REVEL	0.327	indeterminate
SaProt	LLR -10.29	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 1.7	GERP -1.3, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 23 kb · p 5e-10 · regional, not allelic
Overall
CADD	24.5	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 0.00505% Admixed American · 3/59,360 alleles

Filtering AF 0.00134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000672%

Overall 0.00529% 85/1,606,632 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.185%	541
Remaining individualsnot grpmax-eligible	0.0113%	8,872
Admixed Americangrpmax	0.00505%	19,787
African / African-American	0.00268%	37,357
East Asian	0.00223%	44,796
South Asian	0.00221%	45,238
European (non-Finnish)	0.00136%	73,484

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.Arg60Cys
Coding: c.178C>T
MANE Select: NM_004933
dbSNP: rs121434539
Type: single nucleotide variant
Location: chr16:89179551 (GRCh38)
Gene constraint: LOEUF 1.41 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 78.70
Residue 60: a UniProt-annotated variant site (in mrd3; affects cell-cell adhesion but not surface expression of the protein)

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.Arg60His Uncertain significance ★ ⚠ same residue
CDH3 p.Gly60Arg 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

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-arg60cys (accessed [today's date]).

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