# NM_001143992.2(WRAP53):c.31C>T (p.Pro11Ser)

https://sugi.bio/variant/wrap53-p-pro11ser

## Summary

**WRAP53 p.Pro11Ser (c.31C>T)** is classified **Benign/Likely benign** in WRAP53 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0626); Common (popmax 7.83%, afr) — too common for a highly-penetrant pathogenic allele; Associated with dyskeratosis congenita.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs17880282 · 9 submitters · 2 linked conditions · AlphaMissense likely benign · common (popmax 7.83%, afr) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the WRAP53 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 9 submitters, and is linked to dyskeratosis congenita.

*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) |
| Clinical trials | 19 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | WRAP53 is a diagnostic-grade gene on 10 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/0010905/index) · [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.Pro11Ser |
| Coding change (HGVS c.) | c.31C>T |
| MANE Select transcript | [NM_001143992](https://www.ncbi.nlm.nih.gov/nuccore/NM_001143992) |
| dbSNP | [rs17880282](https://www.ncbi.nlm.nih.gov/snp/rs17880282/) |
| Variant type | single nucleotide variant |
| Location | chr17:7688679-7688679 (GRCh38) |
| ClinVar | [VCV325650](https://www.ncbi.nlm.nih.gov/clinvar/variation/325650/) |

**All HGVS expressions:** `LRG_321:g.3872G>A`, `LRG_375:g.7609C>T`, `LRG_375t1:c.31C>T`, `NC_000017.10:g.7591997C>T`, `NC_000017.11:g.7688679C>T`, `NG_017013.2:g.3872G>A`, `NG_028245.1:g.7609C>T`, `NM_001143990.2:c.31C>T`, `NM_001143991.2:c.31C>T`, `NM_001143992.2:c.31C>T`, `NM_018081.2:c.31C>T`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 7.83%, afr) — too common for a highly-penetrant pathogenic allele.

- AlphaMissense **likely benign** (0.0626)
- REVEL 0.063 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.338 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 0.088, GERP -0.637 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 10.35**. 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.*
- Regional missense constraint: **o/e 0.97** across the covering region of the MANE Select transcript (7,688,649–7,702,367), spanning 13,718 bp. Chi-square p 0.54. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for WRAP53 (403 scored positions, the nearest 31 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **7.83%** (afr) · FAF95 7.66% · FAF99 7.59% · 5,874/75,028 in the highest group · 7,259/1,614,206 alleles overall — common (popmax 7.83%, afr) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 7.83% | 13 |
| Admixed American | 0.681% | 147 |
| Remaining individuals (not grpmax-eligible) | 0.635% | 157 |
| Middle Eastern | 0.429% | 233 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.169% | 592 |
| European (non-Finnish) | 0.0399% | 2,505 |
| South Asian | 0.0231% | 4,337 |
| East Asian | 0.02% | 4,988 |
| Finnish (not grpmax-eligible) | 0.00312% | 32,020 |

*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 **11** lies in a UniProt-annotated variant site (in); the 'disordered' region.

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. p.Pro11Ser falls in the disordered region.


### 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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** conflicting (7 Benign, 2 Likely benign).

**Submission history:** 9 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2018-07-09 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Benign | criteria provided, single submitter | clinical testing | 2024-10-10 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-25 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Ambry Genetics | Benign | criteria provided, single submitter | clinical testing | 2016-12-28 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| PreventionGenetics, part of Exact Sciences | Benign | no assertion criteria provided | clinical testing | 2019-07-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2018-07-06 |

## Associated conditions {#conditions}

[dyskeratosis congenita](https://sugi.bio/atlas/disease/dyskeratosis-congenita/), [dyskeratosis congenita, autosomal recessive 3](https://sugi.bio/atlas/disease/dyskeratosis-congenita-autosomal-recessive-3/).

**Reported phenotype names (ClinVar):** Dyskeratosis congenita, not provided, Dyskeratosis congenita, autosomal recessive 3, WRAP53-related disorder, not specified, WRAP53-related condition, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related WRAP53 variant pages (same residue, condition, or type): [WRAP53 p.Pro11Leu](/variant/wrap53-p-pro11leu), [WRAP53 p.Pro11=](/variant/wrap53-p-pro11), [WRAP53 p.Arg265Gln](/variant/wrap53-p-arg265gln), [WRAP53 p.Arg298Gln](/variant/wrap53-p-arg298gln), [WRAP53 p.Arg298Gly](/variant/wrap53-p-arg298gly), [WRAP53 p.Arg298Trp](/variant/wrap53-p-arg298trp), [WRAP53 p.Arg301Cys](/variant/wrap53-p-arg301cys), [WRAP53 p.Arg307Trp](/variant/wrap53-p-arg307trp).

### 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 325650). 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.*