Is CFHR5 p.Cys331Ter (c.993C>A) pathogenic?

CFHR5 p.Cys331Ter (c.993C>A) is classified Conflicting classifications of pathogenicity in CFHR5 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-11-28). Ultra-rare (popmax 0.0957%, sas); Associated with C3 glomerulonephritis.

What condition is associated with CFHR5 p.Cys331Ter (c.993C>A)?

CFHR5 p.Cys331Ter (c.993C>A) is associated with C3 glomerulonephritis (ClinVar).

How common is CFHR5 p.Cys331Ter (c.993C>A) in the general population?

CFHR5 p.Cys331Ter (c.993C>A) is ultra-rare (popmax 0.0957%, sas) (gnomAD).

CFHR5 p.Cys331Ter

c.993C>A · rs751010317 · VCV523049

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0957%, sas)

Conditions

C3 glomerulonephritis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 7 of 10
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.27	GERP -0.79, phastCons 0.061
Overall
CADD	25.3	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 0.0957% South Asian · 81/84,664 alleles

Filtering AF 0.0788% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0726%

Overall 0.00584% 91/1,558,944 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0957%	1,045
Middle Eastern	0.036%	2,778
Remaining individualsnot grpmax-eligible	0.00332%	30,138
European (non-Finnish)	0.000522%	191,488

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.Cys331Ter
Coding: c.993C>A
MANE Select: NM_030787
dbSNP: rs751010317
Type: single nucleotide variant
Location: chr1:196998150 (GRCh38)
Gene constraint: LOEUF 1.466 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.76
Residue 331: a disulfide bond; the sushi 6 domain

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

Disease context

C3 glomerulonephritis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CFHR5 c.607+4A>G Uncertain significance ★★ same condition
CFHR5 p.Arg132Trp Uncertain significance ★★ ⚠ same condition
CFHR5 p.Arg354Gly Uncertain significance ★★ ⚠ same condition
CFHR5 p.Arg435Gln Uncertain significance ★★ ⚠ same condition
CFHR5 p.Arg441Cys Uncertain significance ★★ ⚠ same condition
CFHR5 p.Arg85Gly Uncertain significance ★★ ⚠ same condition
CFHR5 p.Asn126His Uncertain significance ★★ ⚠ same condition
CFHR5 p.Asn230Asp 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/cfhr5-p-cys331ter (accessed [today's date]).

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