Is CFHR3 p.Val318fs (c.952_953insGGAA) pathogenic?

CFHR3 p.Val318fs (c.952953insGGAA) is classified Uncertain significance in CFHR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-29). Very rare (popmax 0.00332%, afr); Associated with hemolytic uremic syndrome, atypical, susceptibility to, 1.

What condition is associated with CFHR3 p.Val318fs (c.952_953insGGAA)?

CFHR3 p.Val318fs (c.952_953insGGAA) is associated with hemolytic uremic syndrome, atypical, susceptibility to, 1 (ClinVar).

How common is CFHR3 p.Val318fs (c.952_953insGGAA) in the general population?

CFHR3 p.Val318fs (c.952_953insGGAA) is very rare (popmax 0.00332%, afr) (gnomAD).

CFHR3 p.Val318fs

c.952_953insGGAA · rs2529661806 · VCV3065621

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 0.00332%, afr)

Conditions

hemolytic uremic syndrome, atypical, susceptibility to, 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 -13	GERP -3.3
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 0.00332% African / African-American · 2/60,270 alleles

Filtering AF 0.00055% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000206%

Overall 0.000216% 3/1,390,616 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00332%	30,135
Remaining individualsnot grpmax-eligible	0.0017%	58,910

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.Val318fs
Coding: c.952_953insGGAA
MANE Select: NM_021023
dbSNP: rs2529661806
Type: Insertion
Location: chr1:196793472 (GRCh38)
Gene constraint: LOEUF 1.302 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.93
Residue 318: a disulfide bond; the sushi 5 domain

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

Disease context

hemolytic uremic syndrome, atypical, susceptibility to, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CFHR3 p.Ile280fs Uncertain significance ★★ same condition
CFHR3 p.Arg142Cys 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
CFHR3 c.613+3_613+6del Pathogenic ★ same condition
CFHR3 p.Gly178= Uncertain significance ★ 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-val318fs (accessed [today's date]).

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