Is CDH15 p.Glu720Ala (c.2159A>C) pathogenic?

CDH15 p.Glu720Ala (c.2159A>C) is classified Conflicting classifications of pathogenicity in CDH15 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-05). AlphaMissense: likely benign (0.0986); Ultra-rare (popmax 0.0219%, amr).

How common is CDH15 p.Glu720Ala (c.2159A>C) in the general population?

CDH15 p.Glu720Ala (c.2159A>C) is ultra-rare (popmax 0.0219%, amr) (gnomAD).

What do computational predictors say about CDH15 p.Glu720Ala (c.2159A>C)?

AlphaMissense predicts likely benign (score 0.0986) — an in-silico prediction, not a clinical call.

CDH15 p.Glu720Ala

c.2159A>C · rs370967218 · VCV210628

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0986 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0219%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0986	likely benign
REVEL	0.173	moderately benign-leaning
SaProt	LLR -7.09	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>G here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.1	GERP -0.33, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 23 kb · p 5e-10 · regional, not allelic
Overall
CADD	21.6	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 0.0219% Admixed American · 13/59,314 alleles

Filtering AF 0.0146% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0139%

Overall 0.0135% 217/1,603,704 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0219%	4,563
European (non-Finnish)	0.0165%	6,057
Remaining individualsnot grpmax-eligible	0.0129%	7,760
African / African-American	0.00268%	37,377

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.Glu720Ala
Coding: c.2159A>C
MANE Select: NM_004933
dbSNP: rs370967218
Type: single nucleotide variant
Location: chr16:89194869 (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.Arg720Ter Pathogenic ★ same residue
CDH3 p.Arg720Gln 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-glu720ala (accessed [today's date]).

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