# NM_002582.4(PARN):c.811dup (p.Ser271fs)

https://sugi.bio/variant/parn-p-ser271fs

## Summary

**PARN p.Ser271fs (c.811dup)** is classified **Pathogenic** in PARN (ClinVar, Single submitter, 1 submitter; last evaluated 2019-03-22). No gnomAD frequency available for this variant.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2151779880 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the PARN gene that is reported as disease-causing, but on limited review, submitted by 1 submitter.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PARN](https://sugi.bio/atlas/gene/PARN/) |
| Protein change (HGVS p.) | p.Ser271fs |
| Coding change (HGVS c.) | c.811dup |
| MANE Select transcript | [NM_002582](https://www.ncbi.nlm.nih.gov/nuccore/NM_002582) |
| dbSNP | [rs2151779880](https://www.ncbi.nlm.nih.gov/snp/rs2151779880/) |
| Variant type | Duplication |
| Location | chr16:14599932-14599933 (GRCh38) |
| ClinVar | [VCV1338503](https://www.ncbi.nlm.nih.gov/clinvar/variation/1338503/) |

**All HGVS expressions:** `LRG_1286:g.35339dup`, `LRG_1286t1:c.811dup`, `NC_000016.10:g.14599936dup`, `NC_000016.9:g.14693793dup`, `NG_042871.1:g.35339dup`, `NM_001134477.3:c.628dup`, `NM_001242992.2:c.673dup`, `NM_002582.4:c.811dup`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 11.722, GERP 2.31, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 12 of 24**, 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: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**PARN** population constraint: LOEUF 0.918, pLI 0.002465, missense-Z -0.2312; 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):

- **pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4** — Definitive (SD)

## Protein context {#protein}

Residue **271** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 81.60, 62% of residues very-high.

**3 experimental structure(s)** (PDB): [2A1R](https://www.rcsb.org/structure/2A1R), [2A1S](https://www.rcsb.org/structure/2A1S), [3CTR](https://www.rcsb.org/structure/3CTR).

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

*Describes the biological roles of PARN (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:** PARN's established molecular role includes RNA binding.


### Pathways affected {#pathways}

PARN participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [ATF4 activates genes in response to endoplasmic reticulum  stress](https://reactome.org/content/detail/R-HSA-380994) | curated |
| [Deadenylation of mRNA](https://reactome.org/content/detail/R-HSA-429947) | curated |
| [KSRP (KHSRP) binds and destabilizes mRNA](https://reactome.org/content/detail/R-HSA-450604) | curated |

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

**Molecular function:** RNA binding, poly(A)-specific ribonuclease activity, protein kinase binding, cation binding, telomerase RNA binding.

**Biological process:** box H/ACA sno(s)RNA 3'-end processing, miRNA catabolic process, positive regulation of telomere maintenance via telomerase, poly(A)-dependent snoRNA 3'-end processing, telomerase RNA stabilization, lncRNA processing.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-03-22.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Pathogenic | criteria provided, single submitter | clinical testing | 2019-03-22 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related PARN variant pages (same residue, condition, or type): [PARN p.Asp292fs](/variant/parn-p-asp292fs), [PARN c.244_245+6dup](/variant/parn-c-244-245-plus-6dup), [PARN c.1006-77dup](/variant/parn-c-1006-minus-77dup), [PARN c.1481-14dup](/variant/parn-c-1481-minus-14dup), [PARN p.Asn420Ter](/variant/parn-p-asn420ter), [PARN p.Asp103fs](/variant/parn-p-asp103fs), [PARN p.Glu189fs](/variant/parn-p-glu189fs), [PARN p.Lys9Ter](/variant/parn-p-lys9ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 1338503). 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.*