CFH

Chr 1ADAR

complement factor H

Also known as: AHUS1, AMBP1, ARMD4, ARMS1, CFHL3, FH, FHL1, HF

NCBI Gene: 3075ENSG00000000971UniProt: P08603

This gene is a member of the Regulator of Complement Activation (RCA) gene cluster and encodes a protein with twenty short consensus repeat (SCR) domains. This protein is secreted into the bloodstream and has an essential role in the regulation of complement activation, restricting this innate defense mechanism to microbial infections. Mutations in this gene have been associated with hemolytic-uremic syndrome (HUS) and chronic hypocomplementemic nephropathy. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Oct 2011]

Primary Disease Associations & Inheritance

{Hemolytic uremic syndrome, atypical, susceptibility to, 1}MIM #235400
ADAR
{Macular degeneration, age-related, 4}MIM #610698
AD
Basal laminar drusenMIM #126700
AD
Complement factor H deficiencyMIM #609814
ADAR
1609
ClinVar variants
46
Pathogenic / LP
0.86
pLI score
2
Active trials
Clinical Summary— CFH
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.86) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
46 Pathogenic / Likely Pathogenic· 241 VUS of 1609 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.32LOEUF
pLI 0.861
Z-score 5.89
OE 0.20 (0.13–0.32)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.00Z-score
OE missense 0.89 (0.83–0.95)
588 obs / 660.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.20 (0.13–0.32)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.89 (0.83–0.95)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.15
0≤1.21.6
LoF obs/exp: 13 / 63.7Missense obs/exp: 588 / 660.1Syn Z: -1.76

ClinVar Variant Classifications

1609 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic28
Likely Pathogenic18
VUS241
Likely Benign30
Benign5
Conflicting12
28
Pathogenic
18
Likely Pathogenic
241
VUS
30
Likely Benign
5
Benign
12
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
13
0
15
0
28
Likely Pathogenic
6
7
5
0
18
VUS
1
218
18
4
241
Likely Benign
0
4
10
16
30
Benign
0
0
5
0
5
Conflicting
—12
Total202295320334

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

CFH · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
COMPLEMENT FACTOR H; CFH
MIM #134370 · *

{Hemolytic uremic syndrome, atypical, susceptibility to, 1}

MIM #235400

Molecular basis of disorder known

Autosomal dominantAutosomal recessive

{Macular degeneration, age-related, 4}

MIM #610698

Molecular basis of disorder known

Autosomal dominant

Basal laminar drusen

MIM #126700

Molecular basis of disorder known

Autosomal dominant

Complement factor H deficiency

MIM #609814

Molecular basis of disorder known

Autosomal dominantAutosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Single-cell RNA and transcriptome sequencing profiles identify immune-associated key genes in the development of diabetic kidney disease.
Zhang X et al.·Front Immunol
2023
Clinical and Genetic Spectrum of a Large Cohort With Total and Sub-total Complement Deficiencies.
El Sissy C et al.·Front Immunol
2019Cohort
Complement factor H polymorphism in age-related macular degeneration.
Klein RJ et al.·Science
2005
Characterization of patients with aHUS and associated triggers or clinical conditions: A Global aHUS Registry analysis.
Licht C et al.·Nephrology (Carlton)
2024Cohort
Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype.
Noris M et al.·Clin J Am Soc Nephrol
2010
The AKT2/SIRT5/TFEB pathway as a potential therapeutic target in non-neovascular AMD.
Ghosh S et al.·Nat Commun
2024
Mesangial C3 Deposition, Complement-Associated Variant, and Disease Progression in IgA Nephropathy.
Kang Y et al.·Clin J Am Soc Nephrol
2023
The spectrum of phenotypes caused by variants in the CFH gene.
Boon CJ et al.·Mol Immunol
2009Review
Update on C3 glomerulopathy.
Barbour TD et al.·Nephrol Dial Transplant
2016Review
Protective coding variants in CFH and PELI3 and a variant near CTRB1 are associated with age-related macular degeneration†.
Yu Y et al.·Hum Mol Genet
2016Meta-analysis
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Meningococcal Meningitis, Serogroup BTransgender PersonsSex Differences in Immune Response

Investigating Gender and Sex Differences in Immune Responses Through Vaccination of Transgender and Cisgender Persons

RECRUITING
NCT06832514Phase PHASE4University GhentStarted 2025-01-31
Serogroup B meningococal vaccine
Mild Cognitive ImpairmentAlzheimer's DiseaseAlzheimer's Disease, Early Onset

Development of a Database to Investigate Digital and Blood-Based Biomarkers and Their Relationship to Tau and Amyloid PET Imaging in Older Participants Who Are Cognitively Normal (CN), Have Mild Cognitive Impairment (MCI), or Have Mild-to-Moderate AD Dementia

RECRUITING
NCT06584357GAP Innovations, PBCStarted 2024-09-26
Biomarker Data CollectionMK6240

External Resources

Links to major genomics databases and tools