# NM_001828.6(CLC):c.389T>G (p.Ile130Ser)

https://sugi.bio/variant/clc-p-ile130ser

## Summary

**CLC p.Ile130Ser (c.389T>G)** is classified **Benign** in CLC (ClinVar, No assertion criteria, 1 submitter; last evaluated 2014-10-31). AlphaMissense: ambiguous (0.5599); Ultra-rare (popmax 0.0201%, eas); Associated with Abnormality of neuronal migration.

**At a glance:** Benign · review: No assertion criteria · rsID rs117361485 · 1 submitter · 1 linked condition · AlphaMissense ambiguous · ultra-rare (popmax 0.0201%, eas)

## For patients & families {#patients}

This is a change in the CLC gene that is classified as benign — not considered disease-causing, submitted by 1 submitter, and is linked to Abnormality of neuronal migration.

*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 | [CLC](https://sugi.bio/atlas/gene/CLC/) |
| Protein change (HGVS p.) | p.Ile130Ser |
| Coding change (HGVS c.) | c.389T>G |
| MANE Select transcript | [NM_013246](https://www.ncbi.nlm.nih.gov/nuccore/NM_013246) (variant reported on NM_001828) |
| dbSNP | [rs117361485](https://www.ncbi.nlm.nih.gov/snp/rs117361485/) |
| Variant type | single nucleotide variant |
| Location | chr19:39731420-39731420 (GRCh38) |
| ClinVar | [VCV208912](https://www.ncbi.nlm.nih.gov/clinvar/variation/208912/) |

**All HGVS expressions:** `NC_000019.10:g.39731420A>C`, `NC_000019.9:g.40222060A>C`, `NG_046978.1:g.11610T>G`, `NM_001828.6:c.389T>G`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; SaProt calls this damaging; REVEL does not; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.5599) — no call either way
- REVEL 0.108 (moderately benign-leaning)
- SaProt LLR -11.612 (damaging)
- → **In-silico consensus:** SaProt calls this damaging; REVEL does not; AlphaMissense makes no call
- Conservation: phyloP 0.795, GERP 0.815 — weakly conserved position
- CADD: **PHRED 19.17**. 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 assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0201%** (eas) · FAF95 0.0104% · FAF99 0.00779% · 9/44,866 in the highest group · 114/1,613,808 alleles overall — ultra-rare (popmax 0.0201%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0201% | 4,985 |
| European (non-Finnish) | 0.00873% | 11,454 |
| Admixed American | 0.00167% | 60,026 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,490 |

*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}

**CLC** population constraint: ClinGen dosage — haploinsufficiency 30, triplosensitivity Not yet evaluated (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}

Residue **130** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 82.59, 60% of residues very-high.

**2 experimental structure(s)** (PDB): [8D7H](https://www.rcsb.org/structure/8D7H), [8D7R](https://www.rcsb.org/structure/8D7R).

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

*Describes the biological roles of CLC (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:** CLC's established molecular role includes signaling receptor binding.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [IL-6-type cytokine receptor ligand interactions](https://reactome.org/content/detail/R-HSA-6788467) | curated |

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

**Molecular function:** signaling receptor binding, cytokine activity, ciliary neurotrophic factor receptor binding.

**Biological process:** cell surface receptor signaling pathway via JAK-STAT, positive regulation of cell population proliferation, cytokine-mediated signaling pathway, negative regulation of neuron apoptotic process, cell surface receptor signaling pathway via STAT.

## Clinical significance {#significance}

**Benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2014-10-31.

**Submitter consensus:** unanimous (1/1 Benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Génétique et pathophysiologie de maladies neurodéveloppementales et épileptogènes, Institut de génétique et de biologie moléculaire et cellulaire | Benign | no assertion criteria provided | clinical testing | 2014-10-31 |

## Associated conditions {#conditions}

[Abnormality of neuronal migration](https://sugi.bio/atlas/disease/abnormality-of-neuronal-migration/).

**Reported phenotype names (ClinVar):** Abnormality of neuronal migration.

## Similar variants {#similar}

Related CLC variant pages (same residue, condition, or type): [CLCF1 p.Arg130His](/variant/clcf1-p-arg130his), [CLCF1 p.Arg130Cys](/variant/clcf1-p-arg130cys), [CLCF1 p.Arg122His](/variant/clcf1-p-arg122his), [CLCF1 p.Arg30His](/variant/clcf1-p-arg30his), [CLCF1 p.Pro38Ser](/variant/clcf1-p-pro38ser), [CLCF1 p.Ser198Leu](/variant/clcf1-p-ser198leu), [CLC p.Asn65Lys](/variant/clc-p-asn65lys), [CLCF1 c.183+14G>A](/variant/clcf1-c-183-plus-14g-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 208912). 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.*