# NM_000562.3(C8A):c.800T>C (p.Val267Ala)

https://sugi.bio/variant/c8a-p-val267ala

## Summary

**C8A p.Val267Ala (c.800T>C)** is classified **Uncertain significance** in C8A (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-25). AlphaMissense: likely benign (0.1042); Ultra-rare (popmax 0.0201%, eas).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs145325749 · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0201%, eas)

## For patients & families {#patients}

This is a change in the C8A 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 | [C8A](https://sugi.bio/atlas/gene/C8A/) |
| Protein change (HGVS p.) | p.Val267Ala |
| Coding change (HGVS c.) | c.800T>C |
| MANE Select transcript | [NM_000562](https://www.ncbi.nlm.nih.gov/nuccore/NM_000562) |
| dbSNP | [rs145325749](https://www.ncbi.nlm.nih.gov/snp/rs145325749/) |
| Variant type | single nucleotide variant |
| Location | chr1:56883626-56883626 (GRCh38) |
| ClinVar | [VCV2048374](https://www.ncbi.nlm.nih.gov/clinvar/variation/2048374/) |

**All HGVS expressions:** `LRG_139:g.33857T>C`, `LRG_139t1:c.800T>C`, `NC_000001.10:g.57349299T>C`, `NC_000001.11:g.56883626T>C`, `NG_012049.1:g.33857T>C`, `NM_000562.3:c.800T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1042)
- REVEL 0.146 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.452 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -0.054, GERP -1.23 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 8.523**. 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 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: **below the reporting threshold**. This position is scored for a different substitution (T>A, Δ0.20 donor 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 **0.0201%** (eas) · FAF95 0.0104% · FAF99 0.00779% · 9/44,866 in the highest group · 13/1,613,816 alleles overall — ultra-rare (popmax 0.0201%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0201% | 4,985 |
| European (non-Finnish) | 0.000339% | 294,982 |

*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 **267** lies in the macpf 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-05-25.

**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 | 2022-05-25 |

**Reported phenotype names (ClinVar):** not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Similar variants {#similar}

Related C8A variant pages (same residue, condition, or type): [C8A p.Arg424Ter](/variant/c8a-p-arg424ter), [C8A p.Arg498Ter](/variant/c8a-p-arg498ter), [C8A p.Glu466Ter](/variant/c8a-p-glu466ter), [C8A p.Tyr210Ter](/variant/c8a-p-tyr210ter), [C8A p.Tyr384Ter](/variant/c8a-p-tyr384ter), [C8A p.Arg107Cys](/variant/c8a-p-arg107cys), [C8A p.Arg196His](/variant/c8a-p-arg196his), [C8A p.Arg207Gln](/variant/c8a-p-arg207gln).

### 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 2048374). 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.*