Is CFH p.Arg175Gln (c.524G>A) pathogenic?

CFH p.Arg175Gln (c.524G>A) is classified Conflicting classifications of pathogenicity in CFH (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-09-17). AlphaMissense: likely benign (0.0847); Very rare (popmax 0.00133%, afr); Associated with age related macular degeneration 4.

What condition is associated with CFH p.Arg175Gln (c.524G>A)?

CFH p.Arg175Gln (c.524G>A) is associated with age related macular degeneration 4 (ClinVar).

How common is CFH p.Arg175Gln (c.524G>A) in the general population?

CFH p.Arg175Gln (c.524G>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about CFH p.Arg175Gln (c.524G>A)?

AlphaMissense predicts likely benign (score 0.0847) — an in-silico prediction, not a clinical call.

CFH p.Arg175Gln

c.524G>A · VCV4291293

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0847 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

age related macular degeneration 4

Computational evidence

Protein change
AlphaMissense	0.0847	likely benign
REVEL	0.649	pathogenic-leaning
SaProt	LLR -6.29	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
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	0.118	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 0.00133% African / African-American · 1/74,958 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000274% 4/1,461,174 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,958
European (non-Finnish)	0.000254%	393,157

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.Arg175Gln
Coding: c.524G>A
MANE Select: NM_000186
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; a disulfide bond; the sushi 3 domain

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

Disease context

age related macular degeneration 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CFH p.Arg175Pro Conflicting classifications of pathogenicity ★ ⚠ same residue
CFH p.Arg175Trp Uncertain significance ★ ⚠ same residue
CFH c.1337-2A>G Likely pathogenic ★★ same condition
CFH c.2236+1G>C Likely pathogenic ★★ same condition
CFH p.Arg1215Ter Pathogenic/Likely pathogenic ★★ same condition
CFH p.Arg53Cys Pathogenic/Likely pathogenic ★★ same condition
CFH p.Cys431Ser Likely pathogenic ★★ same condition
CFH p.Cys611Ter 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-arg175gln (accessed [today's date]).

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