Is CFH p.Arg53Pro (c.158G>C) pathogenic?

CFH p.Arg53Pro (c.158G>C) is classified Uncertain significance in CFH (ClinVar, Single submitter, 1 submitter; last evaluated 2026-09-17). AlphaMissense: likely pathogenic (0.9291); Absent from gnomAD v4.1; Associated with atypical hemolytic-uremic syndrome.

What condition is associated with CFH p.Arg53Pro (c.158G>C)?

CFH p.Arg53Pro (c.158G>C) is associated with atypical hemolytic-uremic syndrome (ClinVar).

How common is CFH p.Arg53Pro (c.158G>C) in the general population?

CFH p.Arg53Pro (c.158G>C) is absent from gnomAD v4.1 (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.Arg53Pro (c.158G>C)?

AlphaMissense predicts likely pathogenic (score 0.9291) — an in-silico prediction, not a clinical call.

CFH p.Arg53Pro

c.158G>C · VCV4291425

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9291 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

atypical hemolytic-uremic syndrome

Computational evidence

Protein change
AlphaMissense	0.9291	likely pathogenic · top 8% in CFH
REVEL	0.435	indeterminate
SaProt	LLR -10.41	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.22	donor loss, 34 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 0.86	GERP -0.59, phastCons 0.2
Regional constraint	o/e 0.99	unconstrained · MANE · 28 kb · p 0.84 · regional, not allelic
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CFH
Protein: p.Arg53Pro
Coding: c.158G>C
MANE Select: NM_000186
Type: single nucleotide variant
Location: chr1:196673077 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 51 PDB
Residue 53: the sushi 1 domain; a disulfide bond

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

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.Arg53Cys Pathogenic/Likely pathogenic ★★ same residue
CFH p.Arg53Ser Likely pathogenic ★ same residue
CFH p.Arg53Gly Uncertain significance ★ ⚠ same residue
CFH p.Arg53His Conflicting classifications of pathogenicity ★ ⚠ same residue
CFH p.Arg53Leu Uncertain significance ★★ ⚠ same residue
CFH p.Arg53= Likely benign ★ same residue
CFH c.1520-1G>A Pathogenic/Likely pathogenic ★★ same condition
CFH c.3493+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-arg53pro (accessed [today's date]).

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