Is CFH p.Arg175Pro (c.524G>C) pathogenic?

CFH p.Arg175Pro (c.524G>C) is classified Conflicting classifications of pathogenicity in CFH (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-10-02). AlphaMissense: likely pathogenic (0.6221); Very rare (popmax 0.00134%, afr); Associated with atypical hemolytic-uremic syndrome.

What condition is associated with CFH p.Arg175Pro (c.524G>C)?

CFH p.Arg175Pro (c.524G>C) is associated with atypical hemolytic-uremic syndrome, basal laminar drusen, hemolytic uremic syndrome, atypical, susceptibility to, 1 (ClinVar).

How common is CFH p.Arg175Pro (c.524G>C) in the general population?

CFH p.Arg175Pro (c.524G>C) is very rare (popmax 0.00134%, afr) (gnomAD).

How is Atypical hemolytic uremic syndrome 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.Arg175Pro (c.524G>C)?

AlphaMissense predicts likely pathogenic (score 0.6221) — an in-silico prediction, not a clinical call.

CFH p.Arg175Pro

c.524G>C · rs139360826 · VCV636726

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.6221 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

atypical hemolytic-uremic syndrome

Computational evidence

Protein change
AlphaMissense	0.6221	likely pathogenic
REVEL	0.377	indeterminate
SaProt	LLR -11.38	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.096	GERP -2.9
Regional constraint	o/e 0.99	unconstrained · MANE · 28 kb · p 0.84 · regional, not allelic
Overall
CADD	12.57	PHRED · no single calibrated threshold — expert panels disagree

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 · 1/74,836 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000496% 8/1,613,118 alleles · very rare exomes 7/1,461,174 · genomes 1/151,944 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,452
African / African-Americangrpmax	0.00134%	74,836
European (non-Finnish)	0.000509%	196,580

Remaining individuals shows a higher raw frequency than the grpmax group above it. 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.

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.Arg175Pro
Coding: c.524G>C
MANE Select: NM_000186
dbSNP: rs139360826
Type: single nucleotide variant
Location: chr1:196677572 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 51 PDB
Residue 175: a β-strand; the sushi 3 domain

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

Disease context

atypical hemolytic-uremic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: basal laminar drusen hemolytic uremic syndrome, atypical, susceptibility to, 1 complement factor H deficiency age related macular degeneration 4

For Atypical hemolytic uremic syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: All ages
Prevalence: 1-9 / 1 000 000 (United States)

Similar variants

CFH p.Arg175Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
CFH p.Arg175Trp 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.350+1G>T Pathogenic/Likely pathogenic ★★ same condition
CFH c.619+1G>A 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-arg175pro (accessed [today's date]).

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