# NM_001710.6(CFB):c.608G>A (p.Arg203Gln)

https://sugi.bio/variant/cfb-p-arg203gln

## Summary

**CFB p.Arg203Gln (c.608G>A)** is classified **Uncertain significance** in CFB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-26). AlphaMissense: ambiguous (0.4657); Very rare (popmax 0.0011%, sas); Associated with atypical hemolytic-uremic syndrome.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs745794224 · 3 submitters · 2 linked conditions · AlphaMissense ambiguous · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the CFB gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 submitters, and is linked to atypical hemolytic-uremic syndrome.

*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 dominant, Autosomal recessive, Not applicable |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-9 / 1 000 000 (United States) |
| Clinical trials | 40 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CFB is a diagnostic-grade gene on 5 Genomics England panels |

**Commonly reported features of Atypical hemolytic uremic syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Proteinuria — Very frequent (99-80%)
- Hematuria — Very frequent (99-80%)
- Abnormality of blood and blood-forming tissues — Very frequent (99-80%)
- Thrombocytopenia — Very frequent (99-80%)
- Acute kidney injury — Very frequent (99-80%)
- Microangiopathic hemolytic anemia — Very frequent (99-80%)
- Abnormality of metabolism/homeostasis — Very frequent (99-80%)
- Abnormal lactate dehydrogenase activity — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0008702/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CFB](https://sugi.bio/atlas/gene/CFB/) |
| Protein change (HGVS p.) | p.Arg203Gln |
| Coding change (HGVS c.) | c.608G>A |
| MANE Select transcript | [NM_001710](https://www.ncbi.nlm.nih.gov/nuccore/NM_001710) |
| dbSNP | [rs745794224](https://www.ncbi.nlm.nih.gov/snp/rs745794224/) |
| Variant type | single nucleotide variant |
| Location | chr6:31947471-31947471 (GRCh38) |
| ClinVar | [VCV2136371](https://www.ncbi.nlm.nih.gov/clinvar/variation/2136371/) |

**All HGVS expressions:** `LRG_136:g.6528G>A`, `LRG_136t1:c.608G>A`, `LRG_26:g.24983G>A`, `NC_000006.11:g.31915248G>A`, `NC_000006.12:g.31947471G>A`, `NG_008191.1:g.6528G>A`, `NG_011730.1:g.24983G>A`, `NG_107817.1:g.246G>A`, `NM_001710.6:c.608G>A`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL make no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.4657) — no call either way
- REVEL 0.457 (indeterminate)
- SaProt LLR -11.759 (damaging)
- Conservation: phyloP 11.851, GERP 1.84, phastCons 1 — highly conserved
- CADD: **PHRED 33.0**. 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** — 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 **0.0011%** (sas) · FAF95 0.000124% · FAF99 9e-05% · 1/91,076 in the highest group · 6/1,460,754 alleles overall — very rare (popmax 0.0011%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0011% | 91,076 |
| European (non-Finnish) | 0.000424% | 236,002 |

*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}

**CFB** population constraint: LOEUF 0.719, pLI 1.4693e-10, missense-Z 2.7519. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **C3 glomerulonephritis** — Limited (AD)
- **atypical hemolytic-uremic syndrome with B factor anomaly** — Moderate (AD)

## Protein context {#protein}

Residue **203** lies in a disulfide bond; a UniProt-annotated variant site (in ahus4); the sushi 3 domain; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 86.54, 65% of residues very-high.

**28 experimental structure(s)** (PDB): [11MG](https://www.rcsb.org/structure/11MG), [11MH](https://www.rcsb.org/structure/11MH), [1DLE](https://www.rcsb.org/structure/1DLE), [1Q0P](https://www.rcsb.org/structure/1Q0P), [1RRK](https://www.rcsb.org/structure/1RRK), [1RS0](https://www.rcsb.org/structure/1RS0).

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

*Describes the biological roles of CFB (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}

CFB participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activation of C3 and C5](https://reactome.org/content/detail/R-HSA-174577) | curated |
| [Alternative complement activation](https://reactome.org/content/detail/R-HSA-173736) | curated |
| [Regulation of Complement cascade](https://reactome.org/content/detail/R-HSA-977606) | curated |

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

**Biological process:** complement activation, alternative pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-09-26.

**Submitter consensus:** unanimous (3/3 Uncertain significance).

**Submission history:** 3 submissions (2021–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-12-20 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Uncertain significance | criteria provided, single submitter | research | 2023-03-15 |
| Genomenon, Inc, Genomenon, Inc | Uncertain significance | criteria provided, single submitter | curation | 2025-09-26 |

## Associated conditions {#conditions}

[atypical hemolytic-uremic syndrome](https://sugi.bio/atlas/disease/atypical-hemolytic-uremic-syndrome/), [atypical hemolytic-uremic syndrome with B factor anomaly](https://sugi.bio/atlas/disease/atypical-hemolytic-uremic-syndrome-with-b-factor-anomaly/).

**Reported phenotype names (ClinVar):** Atypical hemolytic-uremic syndrome, not provided, Atypical hemolytic-uremic syndrome with B factor anomaly, HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 4, AHUS, SUSCEPTIBILITY TO, 4, none provided.

## Similar variants {#similar}

Related CFB variant pages (same residue, condition, or type): [CFB p.Arg203Leu](/variant/cfb-p-arg203leu), [CFB p.Arg203Ter](/variant/cfb-p-arg203ter), [CFB p.Arg203=](/variant/cfb-p-arg203), [CFB c.-3G>A](/variant/cfb-c-minus-3g-a), [CFB p.Arg138Gln](/variant/cfb-p-arg138gln), [CFB p.Arg138Trp](/variant/cfb-p-arg138trp), [CFB p.Arg379Cys](/variant/cfb-p-arg379cys), [CFB p.Gln256Ter](/variant/cfb-p-gln256ter).

### 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 2136371). 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.*