Is CFH p.Arg53His (c.158G>A) pathogenic?

CFH p.Arg53His (c.158G>A) is classified Conflicting classifications of pathogenicity in CFH (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-09-17). AlphaMissense: likely benign (0.2427); Very rare (popmax 0.000678%, nfe); Associated with hemolytic uremic syndrome, atypical, susceptibility to, 1.

What condition is associated with CFH p.Arg53His (c.158G>A)?

CFH p.Arg53His (c.158G>A) is associated with hemolytic uremic syndrome, atypical, susceptibility to, 1, age related macular degeneration 4, atypical hemolytic-uremic syndrome (ClinVar).

How common is CFH p.Arg53His (c.158G>A) in the general population?

CFH p.Arg53His (c.158G>A) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about CFH p.Arg53His (c.158G>A)?

AlphaMissense predicts likely benign (score 0.2427) — an in-silico prediction, not a clinical call.

CFH p.Arg53His

c.158G>A · rs976333015 · VCV2683636

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2427 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hemolytic uremic syndrome, atypical, susceptibility to, 1

Computational evidence

Protein change
AlphaMissense	0.2427	likely benign
REVEL	0.391	indeterminate
SaProt	LLR -9.94	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.22 · evaluated, not missing
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	22.9	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 0.000678% European (non-Finnish) · 8/1,179,860 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000496% 8/1,613,742 alleles · very rare

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.Arg53His
Coding: c.158G>A
MANE Select: NM_000186
dbSNP: rs976333015
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

hemolytic uremic syndrome, atypical, susceptibility to, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: age related macular degeneration 4 atypical hemolytic-uremic syndrome

Similar variants

CFH p.Arg53Cys Pathogenic/Likely pathogenic ★★ same residue
CFH p.Arg53Leu Uncertain significance ★★ ⚠ same residue
CFH p.Arg53Ser Likely pathogenic ★ same residue
CFH p.Arg53Gly Uncertain significance ★ ⚠ same residue
CFH p.Arg53Pro Uncertain significance ★ ⚠ same residue
CFH p.Arg53= Likely benign ★ same residue
CFH c.1337-2A>G Likely pathogenic ★★ same condition
CFH c.1520-1G>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-arg53his (accessed [today's date]).

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