# NM_000562.3(C8A):c.1331G>A (p.Arg444His)

https://sugi.bio/variant/c8a-p-arg444his

## Summary

**C8A p.Arg444His (c.1331G>A)** is classified **Conflicting classifications of pathogenicity** in C8A (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-04-08). AlphaMissense: likely benign (0.1731); Rare (popmax 0.393%, nfe); Associated with type I complement component 8 deficiency.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs143908758 · 9 submitters · 1 linked condition · AlphaMissense likely benign · rare (popmax 0.393%, nfe)

## For patients & families {#patients}

This is a change in the C8A gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 9 submitters, and is linked to type I complement component 8 deficiency.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Diagnostic panels | C8A is a diagnostic-grade gene on 2 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010626/index) · [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.Arg444His |
| Coding change (HGVS c.) | c.1331G>A |
| MANE Select transcript | [NM_000562](https://www.ncbi.nlm.nih.gov/nuccore/NM_000562) |
| dbSNP | [rs143908758](https://www.ncbi.nlm.nih.gov/snp/rs143908758/) |
| Variant type | single nucleotide variant |
| Location | chr1:56908064-56908064 (GRCh38) |
| ClinVar | [VCV789429](https://www.ncbi.nlm.nih.gov/clinvar/variation/789429/) |

**All HGVS expressions:** `LRG_139:g.58295G>A`, `LRG_139t1:c.1331G>A`, `NC_000001.10:g.57373737G>A`, `NC_000001.11:g.56908064G>A`, `NG_012049.1:g.58295G>A`, `NM_000562.3:c.1331G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.1731)
- REVEL 0.861 (moderately pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -5.499 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** REVEL calls this damaging; AlphaMissense and SaProt do not
- Conservation: phyloP 2.766, GERP 0.568, phastCons 0.987 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.3**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.393%** (nfe) · FAF95 0.383% · FAF99 0.379% · 4,635/1,180,000 in the highest group · 5,625/1,614,134 alleles overall — rare (popmax 0.393%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.539% | 186 |
| European (non-Finnish) (grpmax) | 0.393% | 255 |
| Remaining individuals (not grpmax-eligible) | 0.267% | 374 |
| South Asian | 0.26% | 384 |
| Admixed American | 0.22% | 455 |
| African / African-American | 0.128% | 782 |
| Middle Eastern | 0.099% | 1,010 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0236% | 4,229 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **444** lies in a UniProt-annotated variant site (in c8d1); 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-04-08.

**Submitter consensus:** conflicting (6 Likely benign, 3 Uncertain significance).

**Submission history:** 9 submissions (2022–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Uncertain significance | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Uncertain significance | no assertion criteria provided | clinical testing |  |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-04-25 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2022-05-11 |
| Mayo Clinic Laboratories, Mayo Clinic | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-12-16 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-30 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-04-08 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-26 |

## Associated conditions {#conditions}

[type I complement component 8 deficiency](https://sugi.bio/atlas/disease/type-i-complement-component-8-deficiency/).

**Reported phenotype names (ClinVar):** Type I complement component 8 deficiency, not provided, C8A-related disorder, not specified, C8A-related condition, C8AG DEFICIENCY, C8 ALPHA-GAMMA DEFICIENCY, COMPLEMENT C8 DEFICIENCY, TYPE I, none provided, AllHighlyPenetrant.

## 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.Tyr210Ter](/variant/c8a-p-tyr210ter), [C8A p.Tyr384Ter](/variant/c8a-p-tyr384ter), [C8A p.Ile441Val](/variant/c8a-p-ile441val), [C8A p.Lys57Thr](/variant/c8a-p-lys57thr), [C8A p.Pro52Leu](/variant/c8a-p-pro52leu), [C8A p.Ala36Glu](/variant/c8a-p-ala36glu).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 789429). 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.*