Is CDH18 p.Thr219Met (c.656C>T) pathogenic?

CDH18 p.Thr219Met (c.656C>T) is classified Uncertain significance in CDH18 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-08). AlphaMissense: likely benign (0.3084); Very rare (popmax 0.00134%, afr).

How common is CDH18 p.Thr219Met (c.656C>T) in the general population?

CDH18 p.Thr219Met (c.656C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about CDH18 p.Thr219Met (c.656C>T)?

AlphaMissense predicts likely benign (score 0.3084) — an in-silico prediction, not a clinical call.

CDH18 p.Thr219Met

c.656C>T · VCV4223748

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3084 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3084	likely benign
REVEL	0.641	indeterminate
SaProt	LLR -12.85	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 226 kb · p 2.8e-05 · regional, not allelic
Overall
CADD	32.0	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 0.00134% African / African-American · 1/74,818 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000372% 6/1,611,784 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,818
South Asian	0.0011%	91,038
European (non-Finnish)	0.00034%	294,545

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.Thr219Met
Coding: c.656C>T
MANE Select: NM_004934
Type: single nucleotide variant
Location: chr5:19612589 (GRCh38)
Gene constraint: LOEUF 0.737 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.57
Residue 219: the cadherin 2 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-thr219met (accessed [today's date]).

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