Is CFHR5 p.Tyr301= (c.903T>C) pathogenic?

CFHR5 p.Tyr301= (c.903T>C) is classified Conflicting classifications of pathogenicity in CFHR5 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-04-14). Very rare (popmax 0.0022%, sas); Associated with CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II.

How common is CFHR5 p.Tyr301= (c.903T>C) in the general population?

CFHR5 p.Tyr301= (c.903T>C) is very rare (popmax 0.0022%, sas) (gnomAD).

CFHR5 p.Tyr301=

Q: What condition is associated with CFHR5 p.Tyr301= (c.903T>C)?

CFHR5 p.Tyr301= (c.903T>C) is associated with CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II (ClinVar).

c.903T>C · rs886045751 · VCV294548

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Conditions

CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.3	GERP -2.8
Overall
CADD	0.623	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,066 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000137% 2/1,461,100 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.Tyr301=
Coding: c.903T>C
MANE Select: NM_030787
dbSNP: rs886045751
Type: single nucleotide variant
Location: chr1:196996134 (GRCh38)
Gene constraint: LOEUF 1.466 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.76
Residue 301: a disulfide bond; the sushi 5 domain

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

Disease context

CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CFHR5 p.Arg85Gly Uncertain significance ★★ ⚠ same condition
CFHR5 p.Phe192Leu Uncertain significance ★★ ⚠ same condition
CFHR5 p.Pro26Ser Uncertain significance ★★ ⚠ same condition
CFHR5 p.Val430Ala Uncertain significance ★★ ⚠ same condition
CFHR5 c.254-8T>G Benign/Likely benign ★★ same condition
CFHR5 c.-20T>C Benign/Likely benign ★★ same condition
CFHR5 c.*741T>G Benign ★★ same condition
CFHR5 c.*802T>G Benign ★★ 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-tyr301 (accessed [today's date]).

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