# NM_004366.6(CLCN2):c.154C>T (p.Pro52Ser)

https://sugi.bio/variant/clcn2-p-pro52ser

## Summary

**CLCN2 p.Pro52Ser (c.154C>T)** is classified **Conflicting classifications of pathogenicity** in CLCN2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-10-07). AlphaMissense: likely benign (0.069); Very rare (popmax 0.00666%, amr); Associated with Inborn genetic diseases.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs184790106 · 4 submitters · 4 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00666%, amr)

## For patients & families {#patients}

This is a change in the CLCN2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 submitters, 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 | [CLCN2](https://sugi.bio/atlas/gene/CLCN2/) |
| Protein change (HGVS p.) | p.Pro52Ser |
| Coding change (HGVS c.) | c.154C>T |
| MANE Select transcript | [NM_004366](https://www.ncbi.nlm.nih.gov/nuccore/NM_004366) |
| dbSNP | [rs184790106](https://www.ncbi.nlm.nih.gov/snp/rs184790106/) |
| Variant type | single nucleotide variant |
| Location | chr3:184359041-184359041 (GRCh38) |
| ClinVar | [VCV1403342](https://www.ncbi.nlm.nih.gov/clinvar/variation/1403342/) |

**All HGVS expressions:** `NC_000003.11:g.184076829G>A`, `NC_000003.12:g.184359041G>A`, `NG_016422.1:g.7563C>T`, `NM_001171087.3:c.154C>T`, `NM_001171088.3:c.154C>T`, `NM_001171089.3:c.154C>T`, `NM_004366.4:c.154C>T`, `NM_004366.6:c.154C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.069)
- REVEL 0.105 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.444 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 5.749, GERP 1.31, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 13.91**. 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 0.87** across the covering region of the MANE Select transcript (184,346,609–184,361,479), spanning 14,870 bp. Chi-square p 6e-06. 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 (G>T, Δ0.42 donor 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 (gnomAD v4.1): grpmax **0.00666%** (amr) · FAF95 0.00226% · FAF99 0.00135% · 4/60,018 in the highest group · 33/1,613,554 alleles overall — very rare (popmax 0.00666%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00666% | 15,004 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,242 |
| European (non-Finnish) | 0.00229% | 43,705 |

*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}

**CLCN2** population constraint: LOEUF 0.786, pLI 3.1071e-15, missense-Z 2.1216. *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):

- **epilepsy** — Refuted (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 72.82, 34% of residues very-high.

**8 experimental structure(s)** (PDB): [7XF5](https://www.rcsb.org/structure/7XF5), [7XJA](https://www.rcsb.org/structure/7XJA), [8GQU](https://www.rcsb.org/structure/8GQU), [8TA2](https://www.rcsb.org/structure/8TA2), [8TA3](https://www.rcsb.org/structure/8TA3), [8TA4](https://www.rcsb.org/structure/8TA4).

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

*Describes the biological roles of CLCN2 (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:** CLCN2's established molecular role includes voltage-gated chloride channel activity.


### Pathways affected {#pathways}

CLCN2 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:** voltage-gated chloride channel activity, chloride channel regulator activity.

**Biological process:** phagocytosis, engulfment, regulation of aldosterone biosynthetic process.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-10-07.

**Submitter consensus:** conflicting (3 Uncertain significance, 1 Likely benign).

**Submission history:** 4 submissions (2021–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-11-01 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-10-07 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-11-28 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-02-06 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/), [familial hyperaldosteronism type II](https://sugi.bio/atlas/disease/familial-hyperaldosteronism-type-ii/), [epilepsy, idiopathic generalized, susceptibility to, 11](https://sugi.bio/atlas/disease/epilepsy-idiopathic-generalized-susceptibility-to-11/), [leukoencephalopathy with mild cerebellar ataxia and white matter edema](https://sugi.bio/atlas/disease/leukoencephalopathy-with-mild-cerebellar-ataxia-and-white-matter-edema/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not provided, Epilepsy, idiopathic generalized, susceptibility to, 11, Familial hyperaldosteronism type II, Leukoencephalopathy with mild cerebellar ataxia and white matter edema, not specified, AllHighlyPenetrant, FH II, Leukoencephalopathy with ataxia, Leukoencephalopathy with white matter edema.

## Similar variants {#similar}

Related CLCN2 variant pages (same residue, condition, or type): [CLCN2 c.898+1G>A](/variant/clcn2-c-898-plus-1g-a), [CLCN2 p.Arg172Gln](/variant/clcn2-p-arg172gln), [CLCN2 p.Arg610Ter](/variant/clcn2-p-arg610ter), [CLCN2 p.Gly24Asp](/variant/clcn2-p-gly24asp), [CLCN2 p.Trp570Ter](/variant/clcn2-p-trp570ter), [CLCN2 c.1171-3T>C](/variant/clcn2-c-1171-minus-3t-c), [CLCN2 c.1721+4C>T](/variant/clcn2-c-1721-plus-4c-t), [CLCN2 c.1721+5G>A](/variant/clcn2-c-1721-plus-5g-a).

### 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 1403342). 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.*