Is CFHR5 p.Gln520fs (c.1558_1559del) pathogenic?

CFHR5 p.Gln520fs (c.15581559del) is classified Uncertain significance in CFHR5 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-09). Very rare (popmax 0.00267%, afr).

How common is CFHR5 p.Gln520fs (c.1558_1559del) in the general population?

CFHR5 p.Gln520fs (c.1558_1559del) is very rare (popmax 0.00267%, afr) (gnomAD).

CFHR5 p.Gln520fs

c.1558_1559del · rs1279656189 · VCV2682712

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (10 of 10) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.1	GERP -0.81, phastCons 0.27
Overall
CADD	21.1	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,866 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,612,678 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.Gln520fs
Coding: c.1558_1559del
MANE Select: NM_030787
dbSNP: rs1279656189
Type: Deletion
Location: chr1:197008530 (GRCh38)
Gene constraint: LOEUF 1.466 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.76
Residue 520: the sushi 9 domain; a disulfide bond

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

Similar variants

CFHR5 p.Gln520= Conflicting classifications of pathogenicity ★ same residue
CFHR5 p.Asp409fs Uncertain significance ★★ same type
CFHR5 p.Gln250_Cys251delinsArg Uncertain significance ★★ same type
CFHR5 p.Lys329del Uncertain significance ★★ same type
CFHR5 p.Thr21fs Uncertain significance ★★ same type
CFHR5 p.Cys269fs Uncertain significance ★ same type
CFHR5 p.Gln121fs Uncertain significance ★ same type
CFHR5 p.Gln496fs Uncertain significance ★ same type

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-gln520fs (accessed [today's date]).

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