Is PCDH19 p.Pro561= (c.1683G>A) pathogenic?

PCDH19 p.Pro561= (c.1683G>A) is classified Benign/Likely benign in PCDH19 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-04). Rare (popmax 0.437%, mid); Associated with developmental and epileptic encephalopathy, 9.

What condition is associated with PCDH19 p.Pro561= (c.1683G>A)?

PCDH19 p.Pro561= (c.1683G>A) is associated with developmental and epileptic encephalopathy, 9 (ClinVar).

How common is PCDH19 p.Pro561= (c.1683G>A) in the general population?

PCDH19 p.Pro561= (c.1683G>A) is rare (popmax 0.437%, mid) (gnomAD).

PCDH19 p.Pro561=

c.1683G>A · rs192354176 · VCV93672

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

gnomAD v4.1

Rare

rare (popmax 0.437%, mid)

Conditions

developmental and epileptic encephalopathy, 9

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 -5.9	GERP -5.3
Overall
CADD	4.404	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.437% Middle Eastern · 19/4,352 alleles

Filtering AF 0.365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.36%

Overall 0.327% 3,962/1,210,006 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.712%	140
Middle Easterngrpmax	0.437%	229
Remaining individualsnot grpmax-eligible	0.397%	252
European (non-Finnish)	0.375%	266
Admixed American	0.257%	388
Finnishnot grpmax-eligible	0.187%	536
South Asian	0.0423%	2,366
African / African-American	0.0157%	6,359

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: PCDH19
Protein: p.Pro561=
Coding: c.1683G>A
MANE Select: NM_001184880
dbSNP: rs192354176
Type: single nucleotide variant
Location: chrX:100406915 (GRCh38)
Structure: AlphaFold pLDDT 68.50 · 1 PDB
Residue 561: a UniProt-annotated variant site (in dee9); the cadherin 5 domain

Full PCDH19 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

developmental and epileptic encephalopathy, 9 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PCDH19 p.Pro561Ala Pathogenic/Likely pathogenic ★★ same residue
PCDH19 p.Pro561Leu Pathogenic ★★ same residue
PCDH19 p.Pro561Ser Pathogenic ★★ same residue
PCDH19 p.Pro561Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
PCDH19 p.Pro561fs Pathogenic/Likely pathogenic ★★ same residue
PCDH19 c.2675+1G>T Pathogenic/Likely pathogenic ★★ same condition
PCDH19 c.2675+2T>C Pathogenic ★★ same condition
PCDH19 p.Arg198Leu Pathogenic/Likely pathogenic ★★ same condition

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/pcdh19-p-pro561 (accessed [today's date]).

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