Is CFHR5 p.Cys389Phe (c.1166G>T) pathogenic?

CFHR5 p.Cys389Phe (c.1166G>T) is classified Uncertain significance in CFHR5 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-15). AlphaMissense: likely pathogenic (0.9172); Very rare (popmax 0.00356%, nfe); Associated with CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II.

How common is CFHR5 p.Cys389Phe (c.1166G>T) in the general population?

CFHR5 p.Cys389Phe (c.1166G>T) is very rare (popmax 0.00356%, nfe) (gnomAD).

What do computational predictors say about CFHR5 p.Cys389Phe (c.1166G>T)?

AlphaMissense predicts likely pathogenic (score 0.9172) — an in-silico prediction, not a clinical call.

CFHR5 p.Cys389Phe

Q: What condition is associated with CFHR5 p.Cys389Phe (c.1166G>T)?

CFHR5 p.Cys389Phe (c.1166G>T) is associated with CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II (ClinVar).

c.1166G>T · rs138239067 · VCV875557

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9172 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00356%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II

Computational evidence

Protein change
AlphaMissense	0.9172	likely pathogenic · top 6% in CFHR5
REVEL	0.653	pathogenic-leaning
SaProt	LLR -14.96	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.4	GERP 1.8, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 31 kb · p 0.00015 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00356% European (non-Finnish) · 42/1,179,450 alleles

Filtering AF 0.00267% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00236%

Overall 0.0026% 42/1,612,838 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.Cys389Phe
Coding: c.1166G>T
MANE Select: NM_030787
dbSNP: rs138239067
Type: single nucleotide variant
Location: chr1:197002500 (GRCh38)
Gene constraint: LOEUF 1.466 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.76
Residue 389: a disulfide bond; the sushi 7 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.Cys389Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-cys389phe (accessed [today's date]).

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