# NM_001201550.3(CFHR4):c.228T>C (p.Asp76=)

https://sugi.bio/variant/cfhr4-p-asp76

## Summary

**CFHR4 p.Asp76= (c.228T>C)** is classified **Benign/Likely benign** in CFHR4 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-02-01). Low-frequency (popmax 1.4%, nfe); Associated with atypical hemolytic-uremic syndrome.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs145744152 · 6 submitters · 1 linked condition · low-frequency (popmax 1.4%, nfe)

## For patients & families {#patients}

This is a change in the CFHR4 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 6 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 | CFHR4 is a diagnostic-grade gene on 1 Genomics England panel |

**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 | [CFHR4](https://sugi.bio/atlas/gene/CFHR4/) |
| Protein change (HGVS p.) | p.Asp76= |
| Coding change (HGVS c.) | c.228T>C |
| MANE Select transcript | [NM_001201550](https://www.ncbi.nlm.nih.gov/nuccore/NM_001201550) |
| dbSNP | [rs145744152](https://www.ncbi.nlm.nih.gov/snp/rs145744152/) |
| Variant type | single nucleotide variant |
| Location | chr1:196902587-196902587 (GRCh38) |
| ClinVar | [VCV788946](https://www.ncbi.nlm.nih.gov/clinvar/variation/788946/) |

**All HGVS expressions:** `LRG_1224:g.19574T>C`, `LRG_1224t1:c.228T>C`, `NC_000001.10:g.196871717T>C`, `NC_000001.11:g.196902587T>C`, `NG_028159.1:g.19574T>C`, `NM_001201550.3:c.228T>C`, `NM_001201551.2:c.225T>C`, `NM_006684.5:c.228T>C`

## 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 -2.948, GERP -3.69 — fast-evolving / accelerated position
- CADD: **PHRED 0.453**. 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 **1.4%** (nfe) · FAF95 1.39% · FAF99 1.38% · 16,544/1,179,126 in the highest group · 18,597/1,612,242 alleles overall — low-frequency (popmax 1.4%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Amish (not grpmax-eligible) | 1.86% | 54 |
| European (non-Finnish) (grpmax) | 1.4% | 71 |
| Remaining individuals (not grpmax-eligible) | 1.04% | 96 |
| Finnish (not grpmax-eligible) | 0.559% | 179 |
| Admixed American | 0.549% | 182 |
| South Asian | 0.471% | 212 |
| Middle Eastern | 0.248% | 404 |
| African / African-American | 0.247% | 405 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.237% | 423 |
| East Asian | 0.00223% | 44,806 |

Amish 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}

**CFHR4** population constraint: LOEUF 1.204, pLI 1.3755e-19, missense-Z 0.58343. *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 **76** lies in the sushi 1 domain.

AlphaFold model confidence (whole protein): pLDDT 87.75, 51% of residues very-high.

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

*Describes the biological roles of CFHR4 (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}

CFHR4 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Regulation of Complement cascade](https://reactome.org/content/detail/R-HSA-977606) | curated |

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-02-01.

**Submitter consensus:** conflicting (4 Benign, 2 Likely benign).

**Submission history:** 6 submissions (2019–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2019-12-31 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2021-07-08 |
| Genome Diagnostics Laboratory, The Hospital for Sick Children | Likely benign | criteria provided, single submitter | clinical testing | 2020-08-26 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Mayo Clinic Laboratories, Mayo Clinic | Likely benign | criteria provided, single submitter | clinical testing | 2024-12-23 |
| CeGaT Center for Human Genetics Tuebingen | Benign | criteria provided, single submitter | clinical testing | 2025-02-01 |

## Associated conditions {#conditions}

[atypical hemolytic-uremic syndrome](https://sugi.bio/atlas/disease/atypical-hemolytic-uremic-syndrome/).

**Reported phenotype names (ClinVar):** Atypical hemolytic-uremic syndrome, not provided, not specified, none provided, AllHighlyPenetrant.

## Similar variants {#similar}

Related CFHR4 variant pages (same residue, condition, or type): [CFHR4 p.Tyr43Phe](/variant/cfhr4-p-tyr43phe), [CFHR4 p.Ala159Val](/variant/cfhr4-p-ala159val), [CFHR4 p.Arg40His](/variant/cfhr4-p-arg40his), [CFHR4 p.Ile318Thr](/variant/cfhr4-p-ile318thr), [CFHR4 p.Ser199Tyr](/variant/cfhr4-p-ser199tyr), [CFHR4 p.Ser507Leu](/variant/cfhr4-p-ser507leu), [CFHR4 p.Trp68Ter](/variant/cfhr4-p-trp68ter), [CFHR4 p.Tyr238Ser](/variant/cfhr4-p-tyr238ser).

### 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 788946). 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.*