Is PCDH19 p.Phe129Ser (c.386T>C) pathogenic?

PCDH19 p.Phe129Ser (c.386T>C) is classified Uncertain significance in PCDH19 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-07-12). AlphaMissense: likely pathogenic (0.9985); Absent from gnomAD v4.1; Associated with developmental and epileptic encephalopathy, 9.

What condition is associated with PCDH19 p.Phe129Ser (c.386T>C)?

PCDH19 p.Phe129Ser (c.386T>C) is associated with developmental and epileptic encephalopathy, 9 (ClinVar).

How common is PCDH19 p.Phe129Ser (c.386T>C) in the general population?

PCDH19 p.Phe129Ser (c.386T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PCDH19 p.Phe129Ser (c.386T>C)?

AlphaMissense predicts likely pathogenic (score 0.9985) — an in-silico prediction, not a clinical call.

PCDH19 p.Phe129Ser

c.386T>C · rs1602638047 · VCV654172

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9985 · 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	0.9985	likely pathogenic · top 3% in PCDH19
REVEL	0.713	pathogenic-leaning
SaProt	LLR -17.08	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.8, phastCons 1
Regional constraint	o/e 0.25	constrained · MANE · 123 bp · p 7.3e-06 · regional, not allelic
Overall
CADD	28.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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.Phe129Ser
Coding: c.386T>C
MANE Select: NM_001184880
dbSNP: rs1602638047
Type: single nucleotide variant
Location: chrX:100408212 (GRCh38)
Structure: AlphaFold pLDDT 68.50 · 1 PDB
Residue 129: the cadherin 1 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.Phe129Leu Uncertain significance ★ ⚠ same residue
PCDH19 p.Phe129fs 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

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-phe129ser (accessed [today's date]).

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