Is CDH20 p.Asp76Glu (c.228C>A) pathogenic?

CDH20 p.Asp76Glu (c.228C>A) is classified Uncertain significance in CDH20 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-31). AlphaMissense: likely benign (0.119); Ultra-rare (popmax 0.0494%, nfe).

How common is CDH20 p.Asp76Glu (c.228C>A) in the general population?

CDH20 p.Asp76Glu (c.228C>A) is ultra-rare (popmax 0.0494%, nfe) (gnomAD).

What do computational predictors say about CDH20 p.Asp76Glu (c.228C>A)?

AlphaMissense predicts likely benign (score 0.119) — an in-silico prediction, not a clinical call.

CDH20 p.Asp76Glu

c.228C>A · rs139409198 · VCV2220179

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.119 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0494%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.119	likely benign
REVEL	0.203	benign-leaning
SaProt	LLR -7.61	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 -0.13	GERP -2.8, phastCons 0.48
Regional constraint	o/e 0.81	unconstrained · MANE · 60 kb · p 2.3e-07 · regional, not allelic
Overall
CADD	9.086	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0494% European (non-Finnish) · 583/1,179,974 alleles

Filtering AF 0.046% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0448%

Overall 0.0372% 601/1,613,932 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0494%	2,024
Remaining individualsnot grpmax-eligible	0.0144%	6,943
African / African-American	0.00801%	12,486
South Asian	0.0022%	45,535
Admixed American	0.00167%	59,978

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: CDH20
Protein: p.Asp76Glu
Coding: c.228C>A
MANE Select: NM_031891
dbSNP: rs139409198
Type: single nucleotide variant
Location: chr18:61490781 (GRCh38)
Gene constraint: LOEUF 0.532 · pLI 0.72 (gnomAD)
Structure: AlphaFold pLDDT 77.33
Residue 76: the cadherin 1 domain

Full CDH20 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CDH20 p.Arg687Trp Uncertain significance ★★ ⚠ same type
CDH20 p.Pro39= Benign ★★ same type
CDH20 p.Ala226Val Uncertain significance ★ ⚠ same type
CDH20 p.Ala403Val Uncertain significance ★ ⚠ same type
CDH20 p.Ala506Thr Uncertain significance ★ ⚠ same type
CDH20 p.Ala610Val Uncertain significance ★ ⚠ same type
CDH20 p.Ala627Thr Uncertain significance ★ ⚠ same type
CDH20 p.Ala691Thr Uncertain significance ★ ⚠ 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/cdh20-p-asp76glu (accessed [today's date]).

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