# NM_000562.3(C8A):c.213_219del (p.Thr72fs)

https://sugi.bio/variant/c8a-p-thr72fs

## Summary

**C8A p.Thr72fs (c.213_219del)** is classified **Pathogenic** in C8A (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-05). Very rare (popmax 0.00834%, amr).

**At a glance:** Pathogenic · review: Single submitter · rsID rs1259084585 · 1 submitter · very rare (popmax 0.00834%, amr)

## For patients & families {#patients}

This is a change in the C8A gene that is reported as disease-causing, but on limited review, 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 | [C8A](https://sugi.bio/atlas/gene/C8A/) |
| Protein change (HGVS p.) | p.Thr72fs |
| Coding change (HGVS c.) | c.213_219del |
| MANE Select transcript | [NM_000562](https://www.ncbi.nlm.nih.gov/nuccore/NM_000562) |
| dbSNP | [rs1259084585](https://www.ncbi.nlm.nih.gov/snp/rs1259084585/) |
| Variant type | Deletion |
| Location | chr1:56874990-56874996 (GRCh38) |
| ClinVar | [VCV1064346](https://www.ncbi.nlm.nih.gov/clinvar/variation/1064346/) |

**All HGVS expressions:** `LRG_139:g.25221_25227del`, `NC_000001.10:g.57340663_57340669del`, `NC_000001.11:g.56874990_56874996del`, `NG_012049.1:g.25221_25227del`, `NM_000562.3:c.213_219del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 9.84, GERP 2.31, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.168, pLI 1.4084e-23. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 3 of 11**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 32.0**. 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** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00834%** (amr) · FAF95 0.00323% · FAF99 0.00207% · 5/59,966 in the highest group · 6/1,613,610 alleles overall — very rare (popmax 0.00834%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00834% | 11,993 |
| African / African-American | 0.00134% | 74,906 |

*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 **72** lies in a disulfide bond; an α-helix; the tsp type-1 1 domain.

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}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-12-05.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-12-05 |

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

## Similar variants {#similar}

Related C8A variant pages (same residue, condition, or type): [C8A c.655-4del](/variant/c8a-c-655-minus-4del), [C8A p.Ala153fs](/variant/c8a-p-ala153fs), [C8A p.Ala360fs](/variant/c8a-p-ala360fs), [C8A p.Cys194fs](/variant/c8a-p-cys194fs), [C8A p.Ser445del](/variant/c8a-p-ser445del), [C8A p.Val240_Lys241del](/variant/c8a-p-val240-lys241del).

### 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 1064346). 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.*