# NM_001377458.1(CLCC1):c.12T>C (p.Ser4=)

https://sugi.bio/variant/clcc1-p-ser4

## Summary

**CLCC1 p.Ser4= (c.12T>C)** is classified **Uncertain significance** in CLCC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-28). Very rare (popmax 0.000255%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1655039953 · 1 submitter · very rare (popmax 0.000255%, nfe)

## For patients & families {#patients}

This is a change in the CLCC1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [CLCC1](https://sugi.bio/atlas/gene/CLCC1/) |
| Protein change (HGVS p.) | p.Ser4= |
| Coding change (HGVS c.) | c.12T>C |
| MANE Select transcript | [NM_001377458](https://www.ncbi.nlm.nih.gov/nuccore/NM_001377458) |
| dbSNP | [rs1655039953](https://www.ncbi.nlm.nih.gov/snp/rs1655039953/) |
| Variant type | single nucleotide variant |
| Location | chr1:108950426-108950426 (GRCh38) |
| ClinVar | [VCV2119066](https://www.ncbi.nlm.nih.gov/clinvar/variation/2119066/) |

**All HGVS expressions:** `NC_000001.10:g.109493048A>G`, `NC_000001.11:g.108950426A>G`, `NM_001048210.3:c.12T>C`, `NM_001278202.2:c.12T>C`, `NM_001278203.1:c.12T>C`, `NM_001377458.1:c.12T>C`, `NM_001377459.1:c.12T>C`, `NM_001377460.1:c.12T>C`, `NM_001377461.1:c.12T>C`, `NM_001377462.1:c.12T>C`, `NM_001377463.1:c.12T>C`, `NM_001377464.1:c.12T>C`, `NM_001377465.1:c.12T>C`, `NM_001377466.1:c.12T>C`, `NM_001377467.1:c.12T>C`, `NM_001377468.1:c.12T>C`, `NM_001377469.1:c.12T>C`, `NM_001377470.1:c.-451T>C`, `NM_015127.5:c.12T>C`, `NR_165299.1:n.308T>C`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.21) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP -0.616, GERP -3.14 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 5.912**. 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 deltas (raw): acceptor loss **0.21**, donor loss **0.00**, acceptor gain **0.11**, donor gain **0.00**. Largest is acceptor loss, 32 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.22** (gain), gain 0.22 / loss 0.00. SpliceAI calls loss. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.000255%** (nfe) · FAF95 6.8e-05% · FAF99 1.9e-05% · 3/1,176,178 in the highest group · 3/1,607,876 alleles overall — very rare (popmax 0.000255%, nfe).

*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}

**CLCC1** population constraint: LOEUF 0.778, pLI 3.0014e-05, missense-Z 2.0354. *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 61.13, 2% of residues very-high.

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

*Describes the biological roles of CLCC1 (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:** CLCC1's established molecular role includes chloride channel activity.


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

**Molecular function:** chloride channel activity.

**Biological process:** endoplasmic reticulum calcium ion homeostasis.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-03-28.

**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 | 2022-03-28 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related CLCC1 variant pages (same residue, condition, or type): [CLCC1 p.Asp25Glu](/variant/clcc1-p-asp25glu), [CLCC1 p.Ala245Thr](/variant/clcc1-p-ala245thr), [CLCC1 p.Ala522Thr](/variant/clcc1-p-ala522thr), [CLCC1 p.Arg208His](/variant/clcc1-p-arg208his), [CLCC1 p.Arg377Trp](/variant/clcc1-p-arg377trp), [CLCC1 p.Arg381Trp](/variant/clcc1-p-arg381trp), [CLCC1 p.Arg401Gly](/variant/clcc1-p-arg401gly), [CLCC1 p.Arg443Trp](/variant/clcc1-p-arg443trp).

### 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 2119066). 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.*