Is PCDH19 p.Ser403= (c.1209C>T) pathogenic?

PCDH19 p.Ser403= (c.1209C>T) is classified Conflicting classifications of pathogenicity in PCDH19 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-10). Ultra-rare (popmax 0.0608%, afr); Associated with developmental and epileptic encephalopathy, 9.

What condition is associated with PCDH19 p.Ser403= (c.1209C>T)?

PCDH19 p.Ser403= (c.1209C>T) is associated with developmental and epileptic encephalopathy, 9 (ClinVar).

How common is PCDH19 p.Ser403= (c.1209C>T) in the general population?

PCDH19 p.Ser403= (c.1209C>T) is ultra-rare (popmax 0.0608%, afr) (gnomAD).

PCDH19 p.Ser403=

c.1209C>T · rs372006606 · VCV206294

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0608%, afr)

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 3	GERP -1.2, phastCons 1
Overall
CADD	8.25	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0608% African / African-American · 35/57,525 alleles

Filtering AF 0.0449% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0395%

Overall 0.0033% 40/1,211,054 alleles · ultra-rare exomes 20/1,098,144 · genomes 20/112,910 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0608%	1,644
Remaining individualsnot grpmax-eligible	0.0042%	23,818
Admixed American	0.00217%	46,027
European (non-Finnish)	0.000223%	447,716

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.Ser403=
Coding: c.1209C>T
MANE Select: NM_001184880
dbSNP: rs372006606
Type: single nucleotide variant
Location: chrX:100407389 (GRCh38)
Structure: AlphaFold pLDDT 68.50 · 1 PDB
Residue 403: a UniProt-annotated variant site (in dee9); a β-strand; the cadherin 4 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.Ser403fs 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
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

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-ser403 (accessed [today's date]).

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