# NM_000562.3(C8A):c.1454_1455delinsTT (p.Arg485Leu)

https://sugi.bio/variant/c8a-p-arg485leu

## Summary

**C8A p.Arg485Leu (c.1454_1455delinsTT)** is classified **Benign** in C8A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-03). No gnomAD frequency available for this variant.

**At a glance:** Benign · review: Multiple submitters · rsID rs386631447 · 2 submitters · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the C8A gene that is classified as benign — not considered disease-causing, submitted by 2 submitters.

*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 | [C8A](https://sugi.bio/atlas/gene/C8A/) |
| Protein change (HGVS p.) | p.Arg485Leu |
| Coding change (HGVS c.) | c.1454_1455delinsTT |
| MANE Select transcript | [NM_000562](https://www.ncbi.nlm.nih.gov/nuccore/NM_000562) |
| dbSNP | [rs386631447](https://www.ncbi.nlm.nih.gov/snp/rs386631447/) |
| Variant type | Indel |
| Location | chr1:56912476-56912477 (GRCh38) |
| ClinVar | [VCV1169425](https://www.ncbi.nlm.nih.gov/clinvar/variation/1169425/) |

**All HGVS expressions:** `LRG_139:g.62707_62708delinsTT`, `NC_000001.10:g.57378149_57378150delinsTT`, `NC_000001.11:g.56912476_56912477delinsTT`, `NG_012049.1:g.62707_62708delinsTT`, `NM_000562.3:c.1454_1455delinsTT`

## 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 -1.678, GERP -4.03 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Regional missense constraint: **o/e 1.08** across the covering region of the MANE Select transcript (56,854,902–56,917,713), spanning 62,811 bp. Chi-square p 0.034. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no indel variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**C8A** population constraint: LOEUF 1.168, pLI 1.4084e-23, missense-Z -0.23762. *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 **485** lies in a UniProt-annotated variant site (in c8d1); a UniProt-annotated variant site (in); the macpf domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 79.58, 32% of residues very-high.

**11 experimental structure(s)** (PDB): [2QOS](https://www.rcsb.org/structure/2QOS), [2QQH](https://www.rcsb.org/structure/2QQH), [2RD7](https://www.rcsb.org/structure/2RD7), [3OJY](https://www.rcsb.org/structure/3OJY), [6H03](https://www.rcsb.org/structure/6H03), [6H04](https://www.rcsb.org/structure/6H04).

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

*Describes the biological roles of C8A (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}

C8A participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [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:** complement activation, killing of cells of another organism, complement activation, GZMK pathway.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-03.

**Submitter consensus:** unanimous (2/2 Benign).

**Submission history:** 2 submissions (2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-22 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-03 |

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

## Similar variants {#similar}

Related C8A variant pages (same residue, condition, or type): [C8A p.Arg485=](/variant/c8a-p-arg485), [C8A p.Arg485His](/variant/c8a-p-arg485his), [C8A p.Arg485Cys](/variant/c8a-p-arg485cys), [C8A p.Lys401fs](/variant/c8a-p-lys401fs).

### 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 1169425). 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.*