# NM_001734.5(C1S):c.479C>G (p.Pro160Arg)

https://sugi.bio/variant/c1s-p-pro160arg

## Summary

**C1S p.Pro160Arg (c.479C>G)** is classified **Uncertain significance** in C1S (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-05). AlphaMissense: likely benign (0.2871); Very rare (popmax 0.00102%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1400068569 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00102%, nfe)

## For patients & families {#patients}

This is a change in the C1S 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 | [C1S](https://sugi.bio/atlas/gene/C1S/) |
| Protein change (HGVS p.) | p.Pro160Arg |
| Coding change (HGVS c.) | c.479C>G |
| MANE Select transcript | [NM_001734](https://www.ncbi.nlm.nih.gov/nuccore/NM_001734) |
| dbSNP | [rs1400068569](https://www.ncbi.nlm.nih.gov/snp/rs1400068569/) |
| Variant type | single nucleotide variant |
| Location | chr12:7064354-7064354 (GRCh38) |
| ClinVar | [VCV1362375](https://www.ncbi.nlm.nih.gov/clinvar/variation/1362375/) |

**All HGVS expressions:** `LRG_25:g.8679C>G`, `NC_000012.11:g.7171658C>G`, `NC_000012.12:g.7064354C>G`, `NG_011694.1:g.8679C>G`, `NM_001346850.2:c.-23C>G`, `NM_001734.5:c.479C>G`, `NM_201442.4:c.479C>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.2871)
- REVEL 0.538 (indeterminate)
- SaProt LLR -8.34 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 4.799, GERP 1.84, phastCons 0.999 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.2**. 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 0.98** across the covering region of the MANE Select transcript (7,061,913–7,066,551), spanning 4,638 bp. Chi-square p 0.66. 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 (C>A, Δ0.21 acceptor 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 **0.00102%** (nfe) · FAF95 0.000542% · FAF99 0.000428% · 12/1,180,006 in the highest group · 12/1,613,922 alleles overall — very rare (popmax 0.00102%, 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}

**C1S** population constraint: LOEUF 0.783, pLI 0.00018058, missense-Z 2.0076. *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 **160** lies in a disulfide bond; the egf-like; calcium-binding domain.

AlphaFold model confidence (whole protein): pLDDT 88.02, 67% of residues very-high.

**14 experimental structure(s)** (PDB): [1ELV](https://www.rcsb.org/structure/1ELV), [1NZI](https://www.rcsb.org/structure/1NZI), [4J1Y](https://www.rcsb.org/structure/4J1Y), [4LMF](https://www.rcsb.org/structure/4LMF), [4LOR](https://www.rcsb.org/structure/4LOR), [4LOS](https://www.rcsb.org/structure/4LOS).

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

*Describes the biological roles of C1S (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:** C1S's established molecular role includes serine-type endopeptidase activity. p.Pro160Arg falls in the egf-like; calcium-binding domain. In Reactome, C1S is annotated in disease pathway(s) including **Dengue virus activates/modulates innate and adaptive immune responses**.

**Disease mechanism (Reactome):** C1S loss or alteration is curated in [Dengue virus activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9920588).

### Pathways affected {#pathways}

C1S participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Dengue virus activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9920588) | curated |
| [Classical antibody-mediated complement activation](https://reactome.org/content/detail/R-HSA-173623) | curated |
| [Initial triggering of complement](https://reactome.org/content/detail/R-HSA-166663) | curated |
| [Regulation of Complement cascade](https://reactome.org/content/detail/R-HSA-977606) | curated |

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

**Molecular function:** serine-type endopeptidase activity, identical protein binding.

**Biological process:** complement activation, classical pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-10-05.

**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 | 2022-10-05 |

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

## Similar variants {#similar}

Related C1S variant pages (same residue, condition, or type): [C1S p.Pro160Leu](/variant/c1s-p-pro160leu), [C1S p.Pro160=](/variant/c1s-p-pro160), [C1S p.Arg523Ter](/variant/c1s-p-arg523ter), [C1S c.1196-3C>T](/variant/c1s-c-1196-minus-3c-t), [C1S c.717+5G>A](/variant/c1s-c-717-plus-5g-a), [C1S c.717+6T>A](/variant/c1s-c-717-plus-6t-a), [C1S p.Ala227Val](/variant/c1s-p-ala227val), [C1S p.Ala231Val](/variant/c1s-p-ala231val).

### 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 1362375). 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.*