# NM_001184880.2(PCDH19):c.2175C>T (p.Leu725=)

https://sugi.bio/variant/pcdh19-p-leu725

## Summary

**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.

**At a glance:** Likely benign · review: Single submitter · rsID rs777049971 · 1 submitter · 1 linked condition · very rare (popmax 0.00173%, afr)

## For patients & families {#patients}

This is a change in the PCDH19 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to developmental and epileptic encephalopathy, 9.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Diagnostic panels | PCDH19 is a diagnostic-grade gene on 7 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010806/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PCDH19](https://sugi.bio/atlas/gene/PCDH19/) |
| Protein change (HGVS p.) | p.Leu725= |
| Coding change (HGVS c.) | c.2175C>T |
| MANE Select transcript | [NM_001184880](https://www.ncbi.nlm.nih.gov/nuccore/NM_001184880) |
| dbSNP | [rs777049971](https://www.ncbi.nlm.nih.gov/snp/rs777049971/) |
| Variant type | single nucleotide variant |
| Location | chrX:100403637-100403637 (GRCh38) |
| ClinVar | [VCV1627948](https://www.ncbi.nlm.nih.gov/clinvar/variation/1627948/) |

**All HGVS expressions:** `LRG_843:g.11637C>T`, `LRG_843t1:c.2175C>T`, `NC_000023.10:g.99658635G>A`, `NC_000023.11:g.100403637G>A`, `NG_021319.1:g.11637C>T`, `NM_001105243.2:c.2148-786C>T`, `NM_001184880.2:c.2175C>T`, `NM_020766.3:c.2148-786C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.32) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -0.345, GERP -4.99 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 6.69**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI deltas (raw): acceptor loss **0.32**, donor loss **0.00**, acceptor gain **0.15**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.32**, donor loss **0.00**, acceptor gain **0.15**, donor gain **0.00**.
- Pangolin: Δ**0.24** (loss), gain 0.16 / loss 0.24. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00173%** (afr) · FAF95 3.7e-05% · FAF99 1.4e-05% · 1/57,758 in the highest group · 3/1,205,259 alleles overall — very rare (popmax 0.00173%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00173% | 57,758 |
| European (non-Finnish) | 0.000224% | 445,917 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**PCDH19** population constraint: ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **X-linked complex neurodevelopmental disorder** — Definitive (XL)

## Protein context {#protein}

Residue **725** lies in a UniProt-annotated variant site (in dee9).

AlphaFold model confidence (whole protein): pLDDT 68.50, 45% of residues very-high.

**1 experimental structure(s)** (PDB): [6VFU](https://www.rcsb.org/structure/6VFU).

## What this gene does {#gene-function}

*Describes the biological roles of PCDH19 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*


### Pathways affected {#pathways}

PCDH19 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Formation of the nephric duct](https://reactome.org/content/detail/R-HSA-9830364) | electronic |

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-09-03.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-09-03 |

## Associated conditions {#conditions}

[developmental and epileptic encephalopathy, 9](https://sugi.bio/atlas/disease/developmental-and-epileptic-encephalopathy-9/).

**Reported phenotype names (ClinVar):** Developmental and epileptic encephalopathy, 9, Early infantile epileptic encephalopathy 9, EPILEPSY, FEMALE-RESTRICTED, WITH MENTAL RETARDATION, PCDH19-Related X-Linked Female-Limited Epilepsy with Mental Retardation, JUBERG-HELLMAN SYNDROME.

## Similar variants {#similar}

Related PCDH19 variant pages (same residue, condition, or type): [PCDH19 c.2675+1G>T](/variant/pcdh19-c-2675-plus-1g-t), [PCDH19 c.2675+2T>C](/variant/pcdh19-c-2675-plus-2t-c), [PCDH19 p.Arg198Leu](/variant/pcdh19-p-arg198leu), [PCDH19 p.Arg207Ter](/variant/pcdh19-p-arg207ter), [PCDH19 p.Arg372Trp](/variant/pcdh19-p-arg372trp), [PCDH19 p.Arg395Ter](/variant/pcdh19-p-arg395ter), [PCDH19 p.Arg602Ter](/variant/pcdh19-p-arg602ter), [PCDH19 p.Arg886Ter](/variant/pcdh19-p-arg886ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1627948). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*