# NM_001127898.4(CLCN5):c.2320C>T (p.Arg774Ter)

https://sugi.bio/variant/clcn5-p-arg774ter

## Summary

**CLCN5 p.Arg774Ter (c.2320C>T)** is classified **Conflicting classifications of pathogenicity** in CLCN5 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2024-02-16). Very rare (popmax 0.000223%, nfe); Associated with Dent disease type 1.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs151340624 · 6 submitters · 3 linked conditions · very rare (popmax 0.000223%, nfe)

> **Built without this gene's context.** ClinVar files this variant under an overlapping gene, so its own gene's record set does not contain it and this page is assembled from the variant alone. Gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up — absent from this page, not from the data.

## For patients & families {#patients}

This is a change in the CLCN5 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 6 submitters, and is linked to Dent disease type 1.

*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) | X-linked recessive |
| Age of onset (of this condition) | Childhood |

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

- Renal insufficiency — Very frequent (99-80%)
- Renal tubular atrophy — Very frequent (99-80%)
- Proteinuria — Very frequent (99-80%)
- Focal segmental glomerulosclerosis — Very frequent (99-80%)
- Proximal tubulopathy — Very frequent (99-80%)
- Renal phosphate wasting — Very frequent (99-80%)
- Nephrolithiasis — Very frequent (99-80%)
- Hematuria — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0001804/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CLCN5](https://sugi.bio/atlas/gene/CLCN5/) |
| Protein change (HGVS p.) | p.Arg774Ter |
| Coding change (HGVS c.) | c.2320C>T |
| MANE Select transcript | [NM_001127898](https://www.ncbi.nlm.nih.gov/nuccore/NM_001127898) |
| dbSNP | [rs151340624](https://www.ncbi.nlm.nih.gov/snp/rs151340624/) |
| Variant type | single nucleotide variant |
| Location | chrX:50090846-50090846 (GRCh38) |
| ClinVar | [VCV11800](https://www.ncbi.nlm.nih.gov/clinvar/variation/11800/) |

**All HGVS expressions:** `NC_000023.10:g.49855503C>T`, `NC_000023.11:g.50090846C>T`, `NG_007159.3:g.173231C>T`, `NM_000084.4:c.2110C>T`, `NM_000084.5:c.2110C>T`, `NM_001127898.4:c.2320C>T`, `NM_001127899.4:c.2320C>T`, `NM_001282163.2:c.2170C>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 (below), not from a missing predictor score.
- Conservation: phyloP 7.517, GERP 2.73, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. For a truncating variant the loss-of-function impact is position-dependent — C-terminal / last-exon truncations may escape nonsense-mediated decay. *Descriptive; not an applied PVS1 code.*
- CADD: **PHRED 37.0**. 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: **not looked up on this page** — it was served without the gene's SpliceAI index, so no lookup was made. This is a gap in this page, not in the data, and says nothing about whether a splicing effect is predicted.
- Population frequency (gnomAD v4.1): grpmax **0.000223%** (nfe) · FAF95 3.7e-05% · FAF99 1.4e-05% · 2/895,152 in the highest group · 3/1,211,068 alleles overall — very rare (popmax 0.000223%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0021% | 47,631 |
| European (non-Finnish) (grpmax) | 0.000223% | 447,575 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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.*

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-02-16.

**Submitter consensus:** conflicting (4 Pathogenic, 1 Uncertain significance, 1 Likely pathogenic).

**Submission history:** 6 submissions (1996–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Uncertain significance | criteria provided, single submitter | research | 2018-12-03 |
| 3billion | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-02-16 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 1996-02-01 |
| PreventionGenetics, part of Exact Sciences | Pathogenic | no assertion criteria provided | clinical testing | 2023-11-22 |
| MVZ Medizinische Genetik Mainz | Pathogenic | criteria provided, single submitter | clinical testing | 2023-06-05 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2023-11-24 |

## Associated conditions {#conditions}

[Dent disease type 1](https://sugi.bio/atlas/disease/dent-disease-type-1/), [proteinuria, low molecular weight, with hypercalciuria and nephrocalcinosis](https://sugi.bio/atlas/disease/proteinuria-low-molecular-weight-with-hypercalciuria-and-nephrocalcinosis/), [nephrolithiasis, X-linked recessive, with renal failure](https://sugi.bio/atlas/disease/nephrolithiasis-x-linked-recessive-with-renal-failure/).

**Reported phenotype names (ClinVar):** Dent disease type 1, X-linked recessive nephrolithiasis with renal failure, CLCN5-related disorder, Proteinuria, low molecular weight, with hypercalciuria and nephrocalcinosis, NEPHROLITHIASIS 2, NEPHROLITHIASIS, HYPERCALCIURIC, X-LINKED, UROLITHIASIS, X-LINKED RECESSIVE, TYPE 1, NEPHROLITHIASIS 1, NEPHROLITHIASIS, X-LINKED RECESSIVE, TYPE 1, CLCN5-related condition.

### 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 11800). 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.*