# NM_001363.5(DKC1):c.220T>C (p.Cys74Arg)

https://sugi.bio/variant/dkc1-p-cys74arg

## Summary

**DKC1 p.Cys74Arg (c.220T>C)** is classified **Uncertain significance** in DKC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-12). AlphaMissense: ambiguous (0.5344); Absent from gnomAD v4.1; Associated with dyskeratosis congenita.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2148509751 · 1 submitter · 1 linked condition · AlphaMissense ambiguous · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the DKC1 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.

*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 | DKC1 is a diagnostic-grade gene on 18 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 | [DKC1](https://sugi.bio/atlas/gene/DKC1/) |
| Protein change (HGVS p.) | p.Cys74Arg |
| Coding change (HGVS c.) | c.220T>C |
| MANE Select transcript | [NM_001363](https://www.ncbi.nlm.nih.gov/nuccore/NM_001363) |
| dbSNP | [rs2148509751](https://www.ncbi.nlm.nih.gov/snp/rs2148509751/) |
| Variant type | single nucleotide variant |
| Location | chrX:154765955-154765955 (GRCh38) |
| ClinVar | [VCV1444615](https://www.ncbi.nlm.nih.gov/clinvar/variation/1444615/) |

**All HGVS expressions:** `LRG_55:g.8200T>C`, `NC_000023.10:g.153994230T>C`, `NC_000023.11:g.154765955T>C`, `NG_009780.1:g.8200T>C`, `NM_001142463.3:c.220T>C`, `NM_001288747.2:c.220T>C`, `NM_001363.5:c.220T>C`, `NR_110021.2:n.799T>C`, `NR_110022.2:n.322T>C`, `NR_110023.2:n.322T>C`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL make no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.5344) — no call either way
- REVEL 0.474 (indeterminate)
- SaProt LLR -5.979 (tolerated)
- Conservation: phyloP 6.063, GERP 3.89, phastCons 1 — highly conserved
- CADD: **PHRED 19.49**. 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 0.35** across the covering region of the MANE Select transcript (154,762,966–154,767,001), spanning 4,035 bp — the region is depleted of missense variation. Chi-square p 1.8e-12. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (T>G, Δ0.71 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code 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}

**DKC1** population constraint: ClinGen dosage — haploinsufficiency 1, triplosensitivity 0 (0–3 scale). *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):

- **DKC1-related disorder** — Definitive (XL)
- **dyskeratosis congenita, X-linked** — Definitive (XL)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 79.74, 62% 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 DKC1 (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:** DKC1's established molecular role includes telomerase activity.


### Pathways affected {#pathways}

DKC1 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Telomere Extension By Telomerase](https://reactome.org/content/detail/R-HSA-171319) | curated |
| [rRNA modification in the nucleus and cytosol](https://reactome.org/content/detail/R-HSA-6790901) | curated |

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

**Molecular function:** telomerase activity, RNA binding, pseudouridine synthase activity, box H/ACA snoRNA binding, telomerase RNA binding.

**Biological process:** enzyme-directed rRNA pseudouridine synthesis, telomere maintenance via telomerase, positive regulation of telomere maintenance via telomerase, scaRNA localization to Cajal body, telomerase RNA stabilization, regulation of telomerase RNA localization to Cajal body.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-07-12.

**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 | 2021-07-12 |

## Associated conditions {#conditions}

[dyskeratosis congenita](https://sugi.bio/atlas/disease/dyskeratosis-congenita/).

**Reported phenotype names (ClinVar):** Dyskeratosis congenita.

## Similar variants {#similar}

Related DKC1 variant pages (same residue, condition, or type): [DKC1 p.Ala353Val](/variant/dkc1-p-ala353val), [DKC1 p.Asn63Lys](/variant/dkc1-p-asn63lys), [DKC1 p.Thr49Met](/variant/dkc1-p-thr49met), [DKC1 p.Thr66Ala](/variant/dkc1-p-thr66ala), [DKC1 c.1339-10T>G](/variant/dkc1-c-1339-minus-10t-g), [DKC1 c.16+5G>A](/variant/dkc1-c-16-plus-5g-a), [DKC1 c.640+3G>A](/variant/dkc1-c-640-plus-3g-a), [DKC1 p.Ala162Thr](/variant/dkc1-p-ala162thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2026-07-14); 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 1444615). 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.*