# NM_001735.3(C5):c.2103T>C (p.Asp701=)

https://sugi.bio/variant/c5-p-asp701

## Summary

**C5 p.Asp701= (c.2103T>C)** is classified **Likely benign** in C5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-28). Very rare (popmax 0.00446%, eas).

**At a glance:** Likely benign · review: Single submitter · rsID rs183426860 · 1 submitter · very rare (popmax 0.00446%, eas)

## For patients & families {#patients}

This is a change in the C5 gene that is classified as likely benign — not considered disease-causing, 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 | [C5](https://sugi.bio/atlas/gene/C5/) |
| Protein change (HGVS p.) | p.Asp701= |
| Coding change (HGVS c.) | c.2103T>C |
| MANE Select transcript | [NM_001735](https://www.ncbi.nlm.nih.gov/nuccore/NM_001735) |
| dbSNP | [rs183426860](https://www.ncbi.nlm.nih.gov/snp/rs183426860/) |
| Variant type | single nucleotide variant |
| Location | chr9:121014027-121014027 (GRCh38) |
| ClinVar | [VCV2977282](https://www.ncbi.nlm.nih.gov/clinvar/variation/2977282/) |

**All HGVS expressions:** `LRG_28:g.41250T>C`, `LRG_28t1:c.2103T>C`, `NC_000009.11:g.123776305A>G`, `NC_000009.12:g.121014027A>G`, `NG_007364.1:g.41250T>C`, `NM_001317163.2:c.2121T>C`, `NM_001317164.2:c.2103T>C`, `NM_001735.3:c.2103T>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 (below), not from a missing predictor score.
- Conservation: phyloP -0.518, GERP -0.696 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 1.986**. 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: **below the reporting threshold**. This position is scored for a different substitution (A>C, Δ0.23 acceptor loss), 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 **0.00446%** (eas) · FAF95 0.000739% · FAF99 0.000276% · 2/44,886 in the highest group · 4/1,614,186 alleles overall — very rare (popmax 0.00446%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00446% | 22,443 |
| European (non-Finnish) | 0.000169% | 590,012 |

*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}

**C5** population constraint: LOEUF 0.779, pLI 7.7641e-17, missense-Z 2.3738. *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 **701** lies in an α-helix; a UniProt-annotated variant site (in c5d); the anaphylatoxin-like domain; the 'involved in c5ar1 binding' region.

AlphaFold model confidence (whole protein): pLDDT 81.67, 25% of residues very-high.

**49 experimental structure(s)** (PDB): [1CFA](https://www.rcsb.org/structure/1CFA), [1KJS](https://www.rcsb.org/structure/1KJS), [1XWE](https://www.rcsb.org/structure/1XWE), [22CR](https://www.rcsb.org/structure/22CR), [22GK](https://www.rcsb.org/structure/22GK), [22GL](https://www.rcsb.org/structure/22GL).

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

*Describes the biological roles of C5 (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.*


### Pathways affected {#pathways}

C5 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activation of C3 and C5](https://reactome.org/content/detail/R-HSA-174577) | curated |
| [G alpha (i) signalling events](https://reactome.org/content/detail/R-HSA-418594) | curated |
| [Peptide ligand-binding receptors](https://reactome.org/content/detail/R-HSA-375276) | curated |
| [Regulation of Complement cascade](https://reactome.org/content/detail/R-HSA-977606) | curated |
| [Terminal pathway of complement](https://reactome.org/content/detail/R-HSA-166665) | curated |

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

**Biological process:** positive regulation of vascular endothelial growth factor production, negative regulation of macrophage chemotaxis, positive regulation of chemokine production, complement activation, GZMK pathway.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-04-28.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-04-28 |

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

## Similar variants {#similar}

Related C5 variant pages (same residue, condition, or type): [C5 p.Asp701Asn](/variant/c5-p-asp701asn), [C5 p.Asp701Tyr](/variant/c5-p-asp701tyr), [C5 c.2257+1G>A](/variant/c5-c-2257-plus-1g-a), [C5 c.4679-2A>G](/variant/c5-c-4679-minus-2a-g), [C5 p.Arg1476Ter](/variant/c5-p-arg1476ter), [C5 p.Gln19Ter](/variant/c5-p-gln19ter), [C5 p.Glu1437Ter](/variant/c5-p-glu1437ter), [C5 p.Trp469Ter](/variant/c5-p-trp469ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 2977282). 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.*