Is CFH p.Pro503Ala (c.1507C>G) pathogenic?

CFH p.Pro503Ala (c.1507C>G) is classified Uncertain significance in CFH (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-09-17). AlphaMissense: ambiguous (0.3445); Very rare (popmax 0.00204%, nfe); Associated with atypical hemolytic-uremic syndrome.

What condition is associated with CFH p.Pro503Ala (c.1507C>G)?

CFH p.Pro503Ala (c.1507C>G) is associated with atypical hemolytic-uremic syndrome, basal laminar drusen, hemolytic uremic syndrome, atypical, susceptibility to, 1 (ClinVar).

How common is CFH p.Pro503Ala (c.1507C>G) in the general population?

CFH p.Pro503Ala (c.1507C>G) is very rare (popmax 0.00204%, nfe) (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.Pro503Ala (c.1507C>G)?

AlphaMissense predicts ambiguous (score 0.3445) — an in-silico prediction, not a clinical call.

CFH p.Pro503Ala

c.1507C>G · rs570523689 · VCV157562

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.3445 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00204%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

atypical hemolytic-uremic syndrome

Computational evidence

Protein change
AlphaMissense	0.3445	ambiguous
REVEL	0.839	moderately pathogenic-leaning
SaProt	LLR -11.41	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 53 kb · p 0.76 · regional, not allelic
Overall
CADD	23.6	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 0.00204% European (non-Finnish) · 24/1,178,810 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00167% 27/1,612,080 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00204%	49,117
Admixed American	0.00167%	59,842
Remaining individualsnot grpmax-eligible	0.0016%	62,382
African / African-American	0.00134%	74,786

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.Pro503Ala
Coding: c.1507C>G
MANE Select: NM_000186
dbSNP: rs570523689
Type: single nucleotide variant
Location: chr1:196713905 (GRCh38)
Gene constraint: LOEUF 0.43 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.54 · 51 PDB
Residue 503: a disulfide bond; the sushi 8 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 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
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-pro503ala (accessed [today's date]).

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