Is CDH18 p.Thr457Ile (c.1370C>T) pathogenic?

CDH18 p.Thr457Ile (c.1370C>T) is classified Uncertain significance in CDH18 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-27). AlphaMissense: ambiguous (0.3666); Very rare (popmax 0.00117%, sas).

How common is CDH18 p.Thr457Ile (c.1370C>T) in the general population?

CDH18 p.Thr457Ile (c.1370C>T) is very rare (popmax 0.00117%, sas) (gnomAD).

What do computational predictors say about CDH18 p.Thr457Ile (c.1370C>T)?

AlphaMissense predicts ambiguous (score 0.3666) — an in-silico prediction, not a clinical call.

CDH18 p.Thr457Ile

c.1370C>T · VCV3488810

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3666 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00117%, sas)

Computational evidence

Protein change
AlphaMissense	0.3666	ambiguous
REVEL	0.39	indeterminate
SaProt	LLR -9.87	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 139 kb · p 0.64 · regional, not allelic
Overall
CADD	31.0	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 0.00117% South Asian · 1/85,730 alleles

Overall 0.00014% 2/1,429,490 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00117%	85,730
European (non-Finnish)	8.63e-05%	1,159,344

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.Thr457Ile
Coding: c.1370C>T
MANE Select: NM_004934
Type: single nucleotide variant
Location: chr5:19543889 (GRCh38)
Gene constraint: LOEUF 0.737 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.57
Residue 457: the cadherin 4 domain

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

Similar variants

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
CDH18 p.Ala618Thr 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-thr457ile (accessed [today's date]).

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