Is PCDH19 p.Leu725= (c.2175C>T) pathogenic?

PCDH19 p.Leu725= (c.2175C>T) is classified Likely benign in PCDH19 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-03). Very rare (popmax 0.00173%, afr); Associated with developmental and epileptic encephalopathy, 9.

What condition is associated with PCDH19 p.Leu725= (c.2175C>T)?

PCDH19 p.Leu725= (c.2175C>T) is associated with developmental and epileptic encephalopathy, 9 (ClinVar).

How common is PCDH19 p.Leu725= (c.2175C>T) in the general population?

PCDH19 p.Leu725= (c.2175C>T) is very rare (popmax 0.00173%, afr) (gnomAD).

PCDH19 p.Leu725=

c.2175C>T · rs777049971 · VCV1627948

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00173%, afr)

Conditions

developmental and epileptic encephalopathy, 9

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.32	acceptor loss · deltas
Pangolin	Δ0.24	loss · gain 0.16 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -0.34	GERP -5
Overall
CADD	6.69	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00173% African / African-American · 1/57,758 alleles

Filtering AF 3.7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.000275% 3/1,091,603 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00173%	57,758
European (non-Finnish)	0.000224%	445,917

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.Leu725=
Coding: c.2175C>T
MANE Select: NM_001184880
dbSNP: rs777049971
Type: single nucleotide variant
Location: chrX:100403637 (GRCh38)
Structure: AlphaFold pLDDT 68.50 · 1 PDB
Residue 725: a UniProt-annotated variant site (in dee9)

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 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
PCDH19 p.Arg207Ter Pathogenic ★★ same condition
PCDH19 p.Arg372Trp Pathogenic/Likely pathogenic ★★ same condition
PCDH19 p.Arg395Ter Pathogenic ★★ same condition
PCDH19 p.Arg602Ter Pathogenic ★★ same condition
PCDH19 p.Arg886Ter 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-leu725 (accessed [today's date]).

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