Is CDH15 p.Pro485Leu (c.1454C>T) pathogenic?

CDH15 p.Pro485Leu (c.1454C>T) is classified Likely benign in CDH15 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-08-22). AlphaMissense: likely benign (0.0603); Rare (popmax 0.413%, mid).

How common is CDH15 p.Pro485Leu (c.1454C>T) in the general population?

CDH15 p.Pro485Leu (c.1454C>T) is rare (popmax 0.413%, mid) (gnomAD).

What do computational predictors say about CDH15 p.Pro485Leu (c.1454C>T)?

AlphaMissense predicts likely benign (score 0.0603) — an in-silico prediction, not a clinical call.

CDH15 p.Pro485Leu

c.1454C>T · rs533094369 · VCV434636

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0603 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.413%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0603	likely benign
REVEL	0.076	moderately benign-leaning
SaProt	LLR -6.36	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 -0.43	GERP -2.8
Regional constraint	o/e 1.18	unconstrained · MANE · 23 kb · p 5e-10 · regional, not allelic
Overall
CADD	1.755	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 0.413% Middle Eastern · 25/6,056 alleles

Filtering AF 0.287% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.245%

Overall 0.0297% 477/1,603,494 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.413%	242
Remaining individualsnot grpmax-eligible	0.0579%	1,728
Admixed American	0.0435%	2,299
African / African-American	0.0307%	3,260
European (non-Finnish)	0.0294%	3,407
South Asian	0.0209%	4,781
East Asian	0.00447%	22,383

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.Pro485Leu
Coding: c.1454C>T
MANE Select: NM_004933
dbSNP: rs533094369
Type: single nucleotide variant
Location: chr16:89191733 (GRCh38)
Gene constraint: LOEUF 1.41 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 78.70
Residue 485: the cadherin 5 domain

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

Similar variants

CDH15 p.Pro485Arg 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
CDH3 p.Glu708Ter Likely 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-pro485leu (accessed [today's date]).

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