Is CDH15 p.Pro675= (c.2025G>A) pathogenic?

CDH15 p.Pro675= (c.2025G>A) is classified Benign in CDH15 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-09-01). Low-frequency (popmax 1.03%, nfe).

How common is CDH15 p.Pro675= (c.2025G>A) in the general population?

CDH15 p.Pro675= (c.2025G>A) is low-frequency (popmax 1.03%, nfe) (gnomAD).

CDH15 p.Pro675=

c.2025G>A · rs62068507 · VCV128648

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.03%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -9.2	GERP -2.9
Overall
CADD	0.139	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.03% European (non-Finnish) · 12,128/1,179,142 alleles

Filtering AF 1.01% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.01%

Overall 0.87% 13,969/1,605,904 alleles · low-frequency

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	9.32%	11
Ashkenazi Jewishnot grpmax-eligible	1.32%	76
European (non-Finnish)grpmax	1.03%	97
Middle Eastern	0.996%	100
Remaining individualsnot grpmax-eligible	0.869%	115
Admixed American	0.564%	177
South Asian	0.229%	437
African / African-American	0.172%	581
Finnishnot grpmax-eligible	0.17%	590

Amish 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.Pro675=
Coding: c.2025G>A
MANE Select: NM_004933
dbSNP: rs62068507
Type: single nucleotide variant
Location: chr16:89193787 (GRCh38)
Gene constraint: LOEUF 1.41 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 78.70

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

Similar variants

CDH3 p.Leu675Trp 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-pro675 (accessed [today's date]).

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