Is CDH18 p.Thr473Pro (c.1417A>C) pathogenic?

CDH18 p.Thr473Pro (c.1417A>C) is classified Likely benign in CDH18 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-04-15). AlphaMissense: likely benign (0.0583); Rare (popmax 0.261%, eas); Associated with CDH18-related disorder.

What condition is associated with CDH18 p.Thr473Pro (c.1417A>C)?

CDH18 p.Thr473Pro (c.1417A>C) is associated with CDH18-related disorder (ClinVar).

How common is CDH18 p.Thr473Pro (c.1417A>C) in the general population?

CDH18 p.Thr473Pro (c.1417A>C) is rare (popmax 0.261%, eas) (gnomAD).

What do computational predictors say about CDH18 p.Thr473Pro (c.1417A>C)?

AlphaMissense predicts likely benign (score 0.0583) — an in-silico prediction, not a clinical call.

CDH18 p.Thr473Pro

c.1417A>C · rs142033128 · VCV3040449

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0583 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.261%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CDH18-related disorder

Computational evidence

Protein change
AlphaMissense	0.0583	likely benign
REVEL	0.127	moderately benign-leaning
SaProt	LLR -6.50	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 2.5	GERP -2.2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 139 kb · p 0.64 · regional, not allelic
Overall
CADD	14.39	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 0.261% East Asian · 117/44,832 alleles

Filtering AF 0.222% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.208%

Overall 0.0142% 229/1,613,390 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.261%	383
Remaining individualsnot grpmax-eligible	0.141%	710
Admixed American	0.0217%	4,609
South Asian	0.00549%	18,204
African / African-American	0.004%	25,002
European (non-Finnish)	0.000254%	393,190

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: CDH18
Protein: p.Thr473Pro
Coding: c.1417A>C
MANE Select: NM_004934
dbSNP: rs142033128
Type: single nucleotide variant
Location: chr5:19520752 (GRCh38)
Gene constraint: LOEUF 0.737 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.57
Residue 473: the cadherin 4 domain

Full CDH18 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CDH18-related disorder

Similar variants

CDH18 p.Ser647= Likely benign same condition
CDH18 p.Pro386= Benign ★★ same type
CDH18 p.Ser194= Benign ★★ same type
CDH18 p.Ala435Thr Uncertain significance ★ ⚠ same type
CDH18 p.Ala518Asp Uncertain significance ★ ⚠ same type
CDH18 p.Ala602Thr Uncertain significance ★ ⚠ same type
CDH18 p.Ala609Pro Uncertain significance ★ ⚠ same type
CDH18 p.Ala615Gly 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/cdh18-p-thr473pro (accessed [today's date]).

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