# NM_002582.4(PARN):c.270C>T (p.Phe90=)

https://sugi.bio/variant/parn-p-phe90

## Summary

**PARN p.Phe90= (c.270C>T)** is classified **Uncertain significance** in PARN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-22). Absent from gnomAD v4.1; Associated with dyskeratosis congenita, autosomal recessive 6.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1972724336 · 1 submitter · 2 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the PARN gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to dyskeratosis congenita, autosomal recessive 6.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive, X-linked recessive |
| Age of onset (of this condition) | Adolescent, Adult, Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Diagnostic panels | PARN is a diagnostic-grade gene on 14 Genomics England panels |

**Commonly reported features of Dyskeratosis congenita** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hypermelanotic macule — Very frequent (99-80%)
- Abnormal fingernail morphology — Very frequent (99-80%)
- Thrombocytopenia — Very frequent (99-80%)
- Abnormality of neutrophils — Very frequent (99-80%)
- Anemia — Very frequent (99-80%)
- Oral leukoplakia — Very frequent (99-80%)
- Abnormal blistering of the skin — Very frequent (99-80%)
- Nail dystrophy — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016095/index) · [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.Phe90= |
| Coding change (HGVS c.) | c.270C>T |
| MANE Select transcript | [NM_002582](https://www.ncbi.nlm.nih.gov/nuccore/NM_002582) |
| dbSNP | [rs1972724336](https://www.ncbi.nlm.nih.gov/snp/rs1972724336/) |
| Variant type | single nucleotide variant |
| Location | chr16:14627163-14627163 (GRCh38) |
| ClinVar | [VCV1930058](https://www.ncbi.nlm.nih.gov/clinvar/variation/1930058/) |

**All HGVS expressions:** `LRG_1286:g.8109C>T`, `LRG_1286t1:c.270C>T`, `NC_000016.10:g.14627163G>A`, `NC_000016.9:g.14721020G>A`, `NG_042871.1:g.8109C>T`, `NM_001134477.3:c.87C>T`, `NM_001242992.2:c.159-27C>T`, `NM_002582.4:c.270C>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 gain** (Δ 0.24) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 8.539, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 17.42**. 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 **0.02**, donor loss **0.00**, acceptor gain **0.24**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.02**, donor loss **0.00**, acceptor gain **0.24**, donor gain **0.00**.
- Pangolin: Δ**0.24** (loss), gain 0.13 / loss 0.24. SpliceAI calls gain. 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **90** lies in a β-strand.

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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-08-22.

**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 | 2022-08-22 |

## Associated conditions {#conditions}

[dyskeratosis congenita, autosomal recessive 6](https://sugi.bio/atlas/disease/dyskeratosis-congenita-autosomal-recessive-6/), [pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4](https://sugi.bio/atlas/disease/pulmonary-fibrosis-and-or-bone-marrow-failure-telomere-related-4/).

**Reported phenotype names (ClinVar):** Dyskeratosis congenita, autosomal recessive 6, Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4, PULMONARY FIBROSIS AND/OR BONE MARROW FAILURE SYNDROME, TELOMERE-RELATED, 4.

## Similar variants {#similar}

Related PARN variant pages (same residue, condition, or type): [PARN c.1006-2A>G](/variant/parn-c-1006-minus-2a-g), [PARN c.1405+1G>T](/variant/parn-c-1405-plus-1g-t), [PARN c.1481-1G>A](/variant/parn-c-1481-minus-1g-a), [PARN c.178-1G>C](/variant/parn-c-178-minus-1g-c), [PARN c.784-1G>A](/variant/parn-c-784-minus-1g-a), [PARN c.962+2T>C](/variant/parn-c-962-plus-2t-c), [PARN p.Arg128Ter](/variant/parn-p-arg128ter), [PARN p.Arg237Ter](/variant/parn-p-arg237ter).

### 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 1930058). 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.*