# NM_001143992.2(WRAP53):c.1564_1565delinsCG (p.Ala522Arg)

https://sugi.bio/variant/wrap53-p-ala522arg

## Summary

**WRAP53 p.Ala522Arg (c.1564_1565delinsCG)** is classified **Uncertain significance** in WRAP53 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-20). No gnomAD frequency available for this variant.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2074303238 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the WRAP53 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [WRAP53](https://sugi.bio/atlas/gene/WRAP53/) |
| Protein change (HGVS p.) | p.Ala522Arg |
| Coding change (HGVS c.) | c.1564_1565delinsCG |
| MANE Select transcript | [NM_001143992](https://www.ncbi.nlm.nih.gov/nuccore/NM_001143992) |
| dbSNP | [rs2074303238](https://www.ncbi.nlm.nih.gov/snp/rs2074303238/) |
| Variant type | Indel |
| Location | chr17:7703403-7703404 (GRCh38) |
| ClinVar | [VCV1448319](https://www.ncbi.nlm.nih.gov/clinvar/variation/1448319/) |

**All HGVS expressions:** `LRG_375:g.22333_22334delinsCG`, `LRG_375t1:c.1564_1565delinsCG`, `NC_000017.10:g.7606721_7606722delinsCG`, `NC_000017.11:g.7703403_7703404delinsCG`, `NG_028245.1:g.22333_22334delinsCG`, `NM_001143990.2:c.1564_1565delinsCG`, `NM_001143991.2:c.1564_1565delinsCG`, `NM_001143992.2:c.1564_1565delinsCG`, `NM_018081.2:c.1564_1565delinsCG`

## 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 -0.178, GERP -5.08 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Regional missense constraint: **o/e 1.32** across the covering region of the MANE Select transcript (7,703,301–7,703,483), spanning 182 bp. Chi-square p 0.0044. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no indel 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}

**WRAP53** population constraint: LOEUF 0.645, pLI 0.0034137, missense-Z 1.1249; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, 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):

- **dyskeratosis congenita, autosomal recessive 3** — Moderate (AR)

## Protein context {#protein}

Residue **522** lies in a UniProt-annotated variant site (in).

AlphaFold model confidence (whole protein): pLDDT 73.96, 54% of residues very-high.

**7 experimental structure(s)** (PDB): [7BGB](https://www.rcsb.org/structure/7BGB), [7TRC](https://www.rcsb.org/structure/7TRC), [7V9A](https://www.rcsb.org/structure/7V9A), [8OUE](https://www.rcsb.org/structure/8OUE), [8OUF](https://www.rcsb.org/structure/8OUF), [9QB2](https://www.rcsb.org/structure/9QB2).

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

*Describes the biological roles of WRAP53 (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:** WRAP53's established molecular role includes RNA binding.


### Pathways affected {#pathways}

WRAP53 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Telomere Extension By Telomerase](https://reactome.org/content/detail/R-HSA-171319) | curated |
| [Association of TriC/CCT with target proteins during biosynthesis](https://reactome.org/content/detail/R-HSA-390471) | electronic |

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

**Molecular function:** RNA binding, ubiquitin protein ligase binding, histone binding, identical protein binding, protein-containing complex binding, protein-folding chaperone binding.

**Biological process:** telomere maintenance via telomerase, Cajal body organization, telomere formation via telomerase, positive regulation of telomere maintenance via telomerase, RNA folding, positive regulation of DNA repair.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-02-20.

**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 | 2022-02-20 |

**Reported phenotype names (ClinVar):** not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Similar variants {#similar}

Related WRAP53 variant pages (same residue, condition, or type): [WRAP53 p.Ala522Trp](/variant/wrap53-p-ala522trp), [WRAP53 p.Ala522Gly](/variant/wrap53-p-ala522gly), [WRAP53 p.Ala522fs](/variant/wrap53-p-ala522fs), [WRAP53 p.Ala522Thr](/variant/wrap53-p-ala522thr), [WRAP53 p.Ala522Val](/variant/wrap53-p-ala522val), [WRAP53 p.Ala522=](/variant/wrap53-p-ala522), [WRAP53 p.Leu277Val](/variant/wrap53-p-leu277val).

### 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 1448319). 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.*