# NM_003738.5(PTCH2):c.2642dup (p.Pro882fs)

https://sugi.bio/variant/ptch2-p-pro882fs

## Summary

**PTCH2 p.Pro882fs (c.2642dup)** is classified **Uncertain significance** in PTCH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-09-01). Ultra-rare (gnomAD MAF 2.141e-06); Associated with nevoid basal cell carcinoma syndrome.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1337855606 · 1 submitter · 1 linked condition · ultra-rare (gnomAD MAF 2.141e-06)

## For patients & families {#patients}

This is a change in the PTCH2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to nevoid basal cell carcinoma syndrome.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 22 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007166/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PTCH2](https://sugi.bio/atlas/gene/PTCH2/) |
| Protein change (HGVS p.) | p.Pro882fs |
| Coding change (HGVS c.) | c.2642dup |
| MANE Select transcript | [NM_003738](https://www.ncbi.nlm.nih.gov/nuccore/NM_003738) |
| dbSNP | [rs1337855606](https://www.ncbi.nlm.nih.gov/snp/rs1337855606/) |
| Variant type | Duplication |
| Location | chr1:44826954-44826955 (GRCh38) |
| ClinVar | [VCV942904](https://www.ncbi.nlm.nih.gov/clinvar/variation/942904/) |

**All HGVS expressions:** `NC_000001.10:g.45292632dup`, `NC_000001.11:g.44826960dup`, `NG_013369.1:g.20990dup`, `NM_001166292.2:c.2642dup`, `NM_003738.5:c.2642dup`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP -2.453, GERP -3.8 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.895, pLI 1.2554e-24. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 17 of 22**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): global (via dbSNP) **0.000214%** — ultra-rare (gnomAD MAF 2.141e-06).

*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}

**PTCH2** population constraint: LOEUF 0.895, pLI 1.2554e-24, missense-Z 2.16. *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):

- **nevoid basal cell carcinoma syndrome** — Limited (AD)

## Protein context {#protein}

Residue **882** lies in the 'extracellular domain 2 (ecd2)' region.

AlphaFold model confidence (whole protein): pLDDT 79.25, 40% of residues very-high.

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

*Describes the biological roles of PTCH2 (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.*

**How this variant is thought to act:** PTCH2's established molecular role includes smoothened binding. p.Pro882fs falls in the extracellular domain 2 (ecd2) region.


### Pathways affected {#pathways}

PTCH2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Class B/2 (Secretin family receptors)](https://reactome.org/content/detail/R-HSA-373080) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** smoothened binding, hedgehog family protein binding.

**Biological process:** regulation of cell growth.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-09-01.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-09-01 |

## Associated conditions {#conditions}

[nevoid basal cell carcinoma syndrome](https://sugi.bio/atlas/disease/nevoid-basal-cell-carcinoma-syndrome/).

**Reported phenotype names (ClinVar):** Gorlin syndrome, Nevoid Basal Cell Carcinoma Syndrome, Basal cell nevus syndrome.

## Similar variants {#similar}

Related PTCH2 variant pages (same residue, condition, or type): [PTCH2 p.Pro882Ser](/variant/ptch2-p-pro882ser), [PTCH2 p.Pro882=](/variant/ptch2-p-pro882), [PTCH2 c.1685_1709+14dup](/variant/ptch2-c-1685-1709-plus-14dup), [PTCH2 p.Ala131fs](/variant/ptch2-p-ala131fs), [PTCH2 p.Asn509fs](/variant/ptch2-p-asn509fs), [PTCH2 p.Gln271fs](/variant/ptch2-p-gln271fs), [PTCH2 p.Leu221fs](/variant/ptch2-p-leu221fs), [PTCH2 p.Leu524fs](/variant/ptch2-p-leu524fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 942904). 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.*