Is CDH18 p.Val181Met (c.541G>A) pathogenic?

CDH18 p.Val181Met (c.541G>A) is classified Uncertain significance in CDH18 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-17). AlphaMissense: likely pathogenic (0.634); Very rare (popmax 0.000255%, nfe).

How common is CDH18 p.Val181Met (c.541G>A) in the general population?

CDH18 p.Val181Met (c.541G>A) is very rare (popmax 0.000255%, nfe) (gnomAD).

What do computational predictors say about CDH18 p.Val181Met (c.541G>A)?

AlphaMissense predicts likely pathogenic (score 0.634) — an in-silico prediction, not a clinical call.

CDH18 p.Val181Met

c.541G>A · VCV3998873

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.634 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000255%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.634	likely pathogenic
REVEL	0.435	indeterminate
SaProt	LLR -12.87	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.32	acceptor loss at this position · masked 0 · deltas
Constraint at this position
Conservation	phyloP 7.6	GERP 2.6, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 226 kb · p 2.8e-05 · regional, not allelic
Overall
CADD	29.8	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 0.000255% European (non-Finnish) · 3/1,177,800 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000685% 10/1,458,878 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0204%	4,914
Remaining individualsnot grpmax-eligible	0.0016%	62,330
European (non-Finnish)grpmax	0.000255%	392,600

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Val181Met
Coding: c.541G>A
MANE Select: NM_004934
Type: single nucleotide variant
Location: chr5:19721449 (GRCh38)
Gene constraint: LOEUF 0.737 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.57
Residue 181: 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-val181met (accessed [today's date]).

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