Is CFHR5 p.Pro453Ala (c.1357C>G) pathogenic?

CFHR5 p.Pro453Ala (c.1357C>G) is classified Uncertain significance in CFHR5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-20). AlphaMissense: likely benign (0.1766); Very rare (popmax 0.0011%, sas); Associated with C3 glomerulonephritis.

What condition is associated with CFHR5 p.Pro453Ala (c.1357C>G)?

CFHR5 p.Pro453Ala (c.1357C>G) is associated with C3 glomerulonephritis (ClinVar).

How common is CFHR5 p.Pro453Ala (c.1357C>G) in the general population?

CFHR5 p.Pro453Ala (c.1357C>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CFHR5 p.Pro453Ala (c.1357C>G)?

AlphaMissense predicts likely benign (score 0.1766) — an in-silico prediction, not a clinical call.

CFHR5 p.Pro453Ala

c.1357C>G · VCV3576074

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1766 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

C3 glomerulonephritis

Computational evidence

Protein change
AlphaMissense	0.1766	likely benign
REVEL	0.349	indeterminate
SaProt	LLR -12.58	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 1.8, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 31 kb · p 0.00015 · regional, not allelic
Overall
CADD	20.2	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 0.0011% South Asian · 1/91,060 alleles

Overall 6.84e-05% 1/1,461,386 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: CFHR5
Protein: p.Pro453Ala
Coding: c.1357C>G
MANE Select: NM_030787
Type: single nucleotide variant
Location: chr1:197004687 (GRCh38)
Gene constraint: LOEUF 1.466 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.76
Residue 453: a disulfide bond; the sushi 8 domain

Full CFHR5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

C3 glomerulonephritis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CFHR5 p.Pro453Ser Likely benign ★★ ⚠ same residue
CFHR5 c.607+4A>G Uncertain significance ★★ same condition
CFHR5 p.Arg132Trp Uncertain significance ★★ ⚠ same condition
CFHR5 p.Arg354Gly Uncertain significance ★★ ⚠ same condition
CFHR5 p.Arg435Gln Uncertain significance ★★ ⚠ same condition
CFHR5 p.Arg441Cys Uncertain significance ★★ ⚠ same condition
CFHR5 p.Arg85Gly Uncertain significance ★★ ⚠ same condition
CFHR5 p.Asn126His Uncertain significance ★★ ⚠ 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/cfhr5-p-pro453ala (accessed [today's date]).

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