Is CDH18 p.Leu331= (c.991T>C) pathogenic?

CDH18 p.Leu331= (c.991T>C) is classified Uncertain significance in CDH18 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2016-04-27). Common (popmax 21.7%, amr) — too common for a highly-penetrant pathogenic allele; Associated with childhood apraxia of speech.

What condition is associated with CDH18 p.Leu331= (c.991T>C)?

CDH18 p.Leu331= (c.991T>C) is associated with childhood apraxia of speech (ClinVar).

How is Isolated childhood apraxia of speech inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

CDH18 p.Leu331=

Q: How common is CDH18 p.Leu331= (c.991T>C) in the general population?

CDH18 p.Leu331= (c.991T>C) is common (popmax 21.7%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.991T>C · rs17285716 · VCV617842

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 21.7%, amr) — too common for a highly-penetrant pathogenic allele

Conditions

childhood apraxia of speech

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP -2.8, phastCons 1
Overall
CADD	9.145	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 21.7% Admixed American · 11,615/53,644 alleles

Filtering AF 21.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 21.2%

Overall 17.5% 275,676/1,573,662 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	23.7%	4
Finnishnot grpmax-eligible	23.1%	4
Admixed Americangrpmax	21.7%	5
European (non-Finnish)	18.7%	5
South Asian	16.7%	6
Remaining individualsnot grpmax-eligible	16.6%	6
Ashkenazi Jewishnot grpmax-eligible	15.4%	6
Middle Eastern	14.2%	7
African / African-American	4.15%	24
East Asian	0.066%	1,515

Amish 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.Leu331=
Coding: c.991T>C
MANE Select: NM_004934
dbSNP: rs17285716
Type: single nucleotide variant
Location: chr5:19591065 (GRCh38)
Gene constraint: LOEUF 0.737 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.57
Residue 331: the cadherin 3 domain

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

Disease context

childhood apraxia of speech — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Isolated childhood apraxia of speech (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood

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-leu331 (accessed [today's date]).

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