Is CFH p.Leu74Phe (c.220C>T) pathogenic?

CFH p.Leu74Phe (c.220C>T) is classified Uncertain significance in CFH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-09-17). AlphaMissense: likely benign (0.1406); Very rare (popmax 0.00134%, afr); Associated with complement factor H deficiency.

What condition is associated with CFH p.Leu74Phe (c.220C>T)?

CFH p.Leu74Phe (c.220C>T) is associated with complement factor H deficiency, atypical hemolytic-uremic syndrome (ClinVar).

How common is CFH p.Leu74Phe (c.220C>T) in the general population?

CFH p.Leu74Phe (c.220C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

How is Immunodeficiency with factor H anomaly inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CFH p.Leu74Phe (c.220C>T)?

AlphaMissense predicts likely benign (score 0.1406) — an in-silico prediction, not a clinical call.

CFH p.Leu74Phe

c.220C>T · VCV3704360

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1406 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

complement factor H deficiency

Computational evidence

Protein change
AlphaMissense	0.1406	likely benign
REVEL	0.157	moderately benign-leaning
SaProt	LLR -8.73	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.9	GERP -4.1
Regional constraint	o/e 0.99	unconstrained · MANE · 28 kb · p 0.84 · regional, not allelic
Overall
CADD	9.962	PHRED · no single calibrated threshold — expert panels disagree

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

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,832 alleles

Overall 6.2e-05% 1/1,613,288 alleles · very rare exomes 0/1,461,216 · genomes 1/152,072 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: CFH
Protein: p.Leu74Phe
Coding: c.220C>T
MANE Select: NM_000186
Type: single nucleotide variant
Location: chr1:196673139 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 51 PDB
Residue 74: a β-strand; the sushi 1 domain

Full CFH gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

complement factor H deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: atypical hemolytic-uremic syndrome

For Immunodeficiency with factor H anomaly (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive

Similar variants

CFH p.Leu74Val Uncertain significance ★ ⚠ same residue
CFH c.1337-2A>G Likely pathogenic ★★ same condition
CFH c.1520-1G>A Pathogenic/Likely pathogenic ★★ same condition
CFH c.2236+1G>C Likely pathogenic ★★ same condition
CFH c.3493+1G>A Pathogenic/Likely pathogenic ★★ same condition
CFH c.619+1G>A Pathogenic/Likely pathogenic ★★ same condition
CFH p.Arg1215Leu Likely pathogenic ★★ same condition
CFH p.Arg1215Ter Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/cfh-p-leu74phe (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown