Is CFHR5 p.Cys208Arg (c.622T>C) pathogenic?

CFHR5 p.Cys208Arg (c.622T>C) is classified Conflicting classifications of pathogenicity in CFHR5 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-18). AlphaMissense: likely pathogenic (0.9341); Rare (popmax 0.294%, nfe); Associated with CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II.

How common is CFHR5 p.Cys208Arg (c.622T>C) in the general population?

CFHR5 p.Cys208Arg (c.622T>C) is rare (popmax 0.294%, nfe) (gnomAD).

What do computational predictors say about CFHR5 p.Cys208Arg (c.622T>C)?

AlphaMissense predicts likely pathogenic (score 0.9341) — an in-silico prediction, not a clinical call.

CFHR5 p.Cys208Arg

Q: What condition is associated with CFHR5 p.Cys208Arg (c.622T>C)?

CFHR5 p.Cys208Arg (c.622T>C) is associated with CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II, chronic kidney disease (ClinVar).

c.622T>C · rs41299613 · VCV279752

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.9341 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.294%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CFH-Related Dense Deposit Disease / Membranoproliferative Glomerulonephritis Type II

Computational evidence

Protein change
AlphaMissense	0.9341	likely pathogenic · top 5% in CFHR5
REVEL	0.67	pathogenic-leaning
SaProt	LLR -10.49	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 4.7	GERP 1.6, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 31 kb · p 0.00015 · regional, not allelic
Overall
CADD	22.8	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 0.294% European (non-Finnish) · 3,471/1,179,064 alleles

Filtering AF 0.286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.283%

Overall 0.241% 3,890/1,612,986 alleles · rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.439%	228
European (non-Finnish)grpmax	0.294%	340
Remaining individualsnot grpmax-eligible	0.216%	463
South Asian	0.135%	740
Finnishnot grpmax-eligible	0.0984%	1,016
Admixed American	0.0984%	1,017
African / African-American	0.0427%	2,344
Middle Eastern	0.0165%	6,052
East Asian	0.00446%	22,417

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Cys208Arg
Coding: c.622T>C
MANE Select: NM_030787
dbSNP: rs41299613
Type: single nucleotide variant
Location: chr1:196995731 (GRCh38)
Gene constraint: LOEUF 1.466 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.76
Residue 208: a disulfide bond; the sushi 4 domain

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

Disease context

Also linked: chronic kidney disease

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-cys208arg (accessed [today's date]).

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