Is C5 p.Leu758= (c.2272T>C) pathogenic?

C5 p.Leu758= (c.2272T>C) is classified Likely benign in C5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-18). Ultra-rare (popmax 0.0267%, afr); Associated with complement component 5 deficiency.

What condition is associated with C5 p.Leu758= (c.2272T>C)?

C5 p.Leu758= (c.2272T>C) is associated with complement component 5 deficiency (ClinVar).

How common is C5 p.Leu758= (c.2272T>C) in the general population?

C5 p.Leu758= (c.2272T>C) is ultra-rare (popmax 0.0267%, afr) (gnomAD).

C5 p.Leu758=

Q: How is Immunodeficiency due to a late component of complement deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.2272T>C · rs143840189 · VCV721799

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, afr)

Conditions

complement component 5 deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP 0.14, phastCons 0.68
Overall
CADD	6.995	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0267% African / African-American · 20/75,014 alleles

Filtering AF 0.0177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0147%

Overall 0.0013% 21/1,613,114 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0267%	3,751
Remaining individualsnot grpmax-eligible	0.0016%	62,464

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: C5
Protein: p.Leu758=
Coding: c.2272T>C
MANE Select: NM_001735
dbSNP: rs143840189
Type: single nucleotide variant
Location: chr9:121008484 (GRCh38)
Gene constraint: LOEUF 0.779 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.67 · 49 PDB
Residue 758: a β-strand; a disulfide bond; a UniProt-annotated variant site (in c5d)

Full C5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

complement component 5 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Immunodeficiency due to a late component of complement deficiency (Orphanet):

Inheritance: Autosomal recessive

Similar variants

C5 c.2257+1G>A Likely pathogenic ★★ same condition
C5 c.4679-2A>G Likely pathogenic ★★ same condition
C5 p.Arg1476Ter Pathogenic/Likely pathogenic ★★ same condition
C5 p.Gln19Ter Pathogenic ★★ same condition
C5 p.Trp469Ter Pathogenic/Likely pathogenic ★★ same condition
C5 c.2059+3A>G Uncertain significance ★★ same condition
C5 c.4081-6A>G Uncertain significance ★★ same condition
C5 c.4504+4A>G 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/c5-p-leu758 (accessed [today's date]).

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