# NM_000085.5(CLCNKB):c.1346C>G (p.Pro449Arg)

https://sugi.bio/variant/clcnkb-p-pro449arg

## Summary

**CLCNKB p.Pro449Arg (c.1346C>G)** is classified **Uncertain significance** in CLCNKB (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-26). AlphaMissense: likely benign (0.1771); Very rare (popmax 0.000137%); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2023302493 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.000137%)

## For patients & families {#patients}

This is a change in the CLCNKB gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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 | [CLCNKB](https://sugi.bio/atlas/gene/CLCNKB/) |
| Protein change (HGVS p.) | p.Pro449Arg |
| Coding change (HGVS c.) | c.1346C>G |
| MANE Select transcript | [NM_000085](https://www.ncbi.nlm.nih.gov/nuccore/NM_000085) |
| dbSNP | [rs2023302493](https://www.ncbi.nlm.nih.gov/snp/rs2023302493/) |
| Variant type | single nucleotide variant |
| Location | chr1:16051758-16051758 (GRCh38) |
| ClinVar | [VCV2401566](https://www.ncbi.nlm.nih.gov/clinvar/variation/2401566/) |

**All HGVS expressions:** `NC_000001.10:g.16378253C>G`, `NC_000001.11:g.16051758C>G`, `NG_013079.1:g.13007C>G`, `NG_013079.2:g.12978C>G`, `NG_042865.1:g.7266C>G`, `NM_000085.5:c.1346C>G`, `NM_001165945.2:c.839C>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.1771)
- REVEL 0.726 (pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -12.244 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** REVEL and SaProt call this damaging; AlphaMissense does not
- SpliceAI predicts **acceptor gain** (Δ 0.26) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.439, GERP 2.05, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.9**. 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 0.89** across the covering region of the MANE Select transcript (16,044,493–16,056,913), spanning 12,420 bp. Chi-square p 0.0014. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.15**, donor loss **0.00**, acceptor gain **0.26**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.26**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): global (via dbSNP) **0.000137%** · 2/1,461,738 alleles overall — very rare (popmax 0.000137%).

*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}

**CLCNKB** population constraint: LOEUF 1.072, pLI 1.4731e-22, missense-Z 1.2899; ClinGen dosage — haploinsufficiency 30, 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.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 87.16, 60% of residues very-high.

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

*Describes the biological roles of CLCNKB (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:** CLCNKB's established molecular role includes chloride channel activity.


### Pathways affected {#pathways}

CLCNKB participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Stimuli-sensing channels](https://reactome.org/content/detail/R-HSA-2672351) | curated |

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

**Molecular function:** chloride channel activity.

**Biological process:** renal sodium ion absorption.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-01-26.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-01-26 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related CLCNKB variant pages (same residue, condition, or type): [CLCNKB p.Ala178Val](/variant/clcnkb-p-ala178val), [CLCNKB p.Ala488Asp](/variant/clcnkb-p-ala488asp), [CLCNKB p.Arg27Cys](/variant/clcnkb-p-arg27cys), [CLCNKB p.Arg346His](/variant/clcnkb-p-arg346his), [CLCNKB p.Asp363Asn](/variant/clcnkb-p-asp363asn), [CLCNKB p.Cys617Tyr](/variant/clcnkb-p-cys617tyr), [CLCNKB p.Gly493Ser](/variant/clcnkb-p-gly493ser), [CLCNKB p.Gly625Val](/variant/clcnkb-p-gly625val).

### 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 2401566). 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.*