Is CFHR3 p.Ile280fs (c.839_840del) pathogenic?

CFHR3 p.Ile280fs (c.839840del) is classified Uncertain significance in CFHR3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-14). Rare (popmax 0.193%, nfe); Associated with age related macular degeneration 1.

What condition is associated with CFHR3 p.Ile280fs (c.839_840del)?

CFHR3 p.Ile280fs (c.839_840del) is associated with age related macular degeneration 1, hemolytic uremic syndrome, atypical, susceptibility to, 1 (ClinVar).

How common is CFHR3 p.Ile280fs (c.839_840del) in the general population?

CFHR3 p.Ile280fs (c.839_840del) is rare (popmax 0.193%, nfe) (gnomAD).

CFHR3 p.Ile280fs

c.839_840del · rs781400776 · VCV1163768

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

rare (popmax 0.193%, nfe)

Conditions

age related macular degeneration 1

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 (6 of 6) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -5.9	GERP -0.84
Overall
CADD	23.2	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	seg dup	· reads may not map uniquely · confidence, not pathogenicity

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.193% European (non-Finnish) · 2,174/1,123,928 alleles

Filtering AF 0.187% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.184%

Overall 0.156% 2,365/1,519,668 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.193%	517
Remaining individualsnot grpmax-eligible	0.161%	622
Admixed American	0.13%	770
Middle Eastern	0.0379%	2,638
African / African-American	0.0183%	5,462
South Asian	0.00996%	10,042
Finnishnot grpmax-eligible	0.00163%	61,358

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: CFHR3
Protein: p.Ile280fs
Coding: c.839_840del
MANE Select: NM_021023
dbSNP: rs781400776
Type: Deletion
Location: chr1:196793358 (GRCh38)
Gene constraint: LOEUF 1.302 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.93
Residue 280: a disulfide bond; the sushi 5 domain

Full CFHR3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: hemolytic uremic syndrome, atypical, susceptibility to, 1

Similar variants

CFHR3 c.613+3_613+6del Pathogenic ★ same condition
CFHR3 p.Phe34fs Uncertain significance ★ same condition
CFHR3 p.Arg142Cys Benign ★★ ⚠ same condition
CFHR3 p.Cys268Phe Likely benign ★★ same condition
CFHR3 p.Gln240His Benign ★★ ⚠ same condition
CFHR3 p.Ile269Val Likely benign ★★ same condition
CFHR3 p.Ile312Phe Benign/Likely benign ★★ same condition
CFHR3 p.Phe34Cys Benign/Likely 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/cfhr3-p-ile280fs (accessed [today's date]).

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