Is CDH20 p.Pro740Ser (c.2218C>T) pathogenic?

CDH20 p.Pro740Ser (c.2218C>T) is classified Uncertain significance in CDH20 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-17). AlphaMissense: likely pathogenic (0.5652); Very rare (popmax 0.00501%, amr).

How common is CDH20 p.Pro740Ser (c.2218C>T) in the general population?

CDH20 p.Pro740Ser (c.2218C>T) is very rare (popmax 0.00501%, amr) (gnomAD).

What do computational predictors say about CDH20 p.Pro740Ser (c.2218C>T)?

AlphaMissense predicts likely pathogenic (score 0.5652) — an in-silico prediction, not a clinical call.

CDH20 p.Pro740Ser

c.2218C>T · VCV3265245

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5652 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00501%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5652	likely pathogenic
REVEL	0.772	pathogenic-leaning
SaProt	LLR -10.24	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 1.9, phastCons 0.99
Regional constraint	o/e 1.28	unconstrained · MANE · 4,569 bp · p 1.7e-06 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00501% Admixed American · 3/59,936 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000248% 4/1,612,746 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00501%	19,979
African / African-American	0.00133%	74,928

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.Pro740Ser
Coding: c.2218C>T
MANE Select: NM_031891
Type: single nucleotide variant
Location: chr18:61554507 (GRCh38)
Gene constraint: LOEUF 0.532 · pLI 0.72 (gnomAD)
Structure: AlphaFold pLDDT 77.33

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-pro740ser (accessed [today's date]).

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