Is CDH15 p.Asp668Asn (c.2002G>A) pathogenic?

CDH15 p.Asp668Asn (c.2002G>A) is classified Uncertain significance in CDH15 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-26). AlphaMissense: likely benign (0.1375); Very rare (popmax 0.000254%, nfe).

How common is CDH15 p.Asp668Asn (c.2002G>A) in the general population?

CDH15 p.Asp668Asn (c.2002G>A) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about CDH15 p.Asp668Asn (c.2002G>A)?

AlphaMissense predicts likely benign (score 0.1375) — an in-silico prediction, not a clinical call.

CDH15 p.Asp668Asn

c.2002G>A · VCV4223682

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1375 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1375	likely benign
REVEL	0.382	indeterminate
SaProt	LLR -10.36	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 11	GERP 0.29, phastCons 1
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 0.000254% European (non-Finnish) · 3/1,178,862 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000413% 6/1,451,820 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00522%	19,159
European (non-Finnish)grpmax	0.000254%	392,954

Finnish 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.Asp668Asn
Coding: c.2002G>A
MANE Select: NM_004933
Type: single nucleotide variant
Location: chr16:89193764 (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 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
CDH3 p.Trp362Ter 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-asp668asn (accessed [today's date]).

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