Is PCDH19 p.Pro451Ser (c.1351C>T) pathogenic?

PCDH19 p.Pro451Ser (c.1351C>T) is classified Conflicting classifications of pathogenicity in PCDH19 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-11-07). AlphaMissense: likely pathogenic (0.9995); Absent from gnomAD v4.1; Associated with developmental and epileptic encephalopathy, 9.

What condition is associated with PCDH19 p.Pro451Ser (c.1351C>T)?

PCDH19 p.Pro451Ser (c.1351C>T) is associated with developmental and epileptic encephalopathy, 9 (ClinVar).

How common is PCDH19 p.Pro451Ser (c.1351C>T) in the general population?

PCDH19 p.Pro451Ser (c.1351C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PCDH19 p.Pro451Ser (c.1351C>T)?

AlphaMissense predicts likely pathogenic (score 0.9995) — an in-silico prediction, not a clinical call.

PCDH19 p.Pro451Ser

c.1351C>T · rs796052816 · VCV206332

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9995 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

developmental and epileptic encephalopathy, 9

Computational evidence

Protein change
AlphaMissense	0.9995	likely pathogenic · top 1% in PCDH19
REVEL	0.829	moderately pathogenic-leaning
SaProt	LLR -12.73	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.8, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 1,099 bp · p 7e-14 · regional, not allelic
Overall
CADD	26.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PCDH19
Protein: p.Pro451Ser
Coding: c.1351C>T
MANE Select: NM_001184880
dbSNP: rs796052816
Type: single nucleotide variant
Location: chrX:100407247 (GRCh38)
Structure: AlphaFold pLDDT 68.50 · 1 PDB
Residue 451: a UniProt-annotated variant site (in dee9); 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.Pro451Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
PCDH19 p.Pro451Thr Uncertain significance ★ ⚠ same residue
PCDH19 p.Pro451= Likely benign ★ 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

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-pro451ser (accessed [today's date]).

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