Is C5 p.Arg1476Ter (c.4426C>T) pathogenic?

C5 p.Arg1476Ter (c.4426C>T) is classified Pathogenic/Likely pathogenic in C5 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-08). Ultra-rare (popmax 0.0347%, afr); Associated with C5-related disorders.

What condition is associated with C5 p.Arg1476Ter (c.4426C>T)?

C5 p.Arg1476Ter (c.4426C>T) is associated with C5-related disorders, complement component 5 deficiency (ClinVar).

How common is C5 p.Arg1476Ter (c.4426C>T) in the general population?

C5 p.Arg1476Ter (c.4426C>T) is ultra-rare (popmax 0.0347%, afr) (gnomAD).

C5 p.Arg1476Ter

c.4426C>T · rs121909588 · VCV17051

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0347%, afr)

Conditions

C5-related disorders

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 36 of 41
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.26 · evaluated, not missing
Pangolin	Δ0.20	loss · gain 0.01 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 8.6	GERP 1.4, phastCons 1
Overall
CADD	42.0	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 0.0347% African / African-American · 26/74,902 alleles

Filtering AF 0.0243% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0208%

Overall 0.00694% 112/1,613,830 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0347%	2,881
Remaining individualsnot grpmax-eligible	0.016%	6,248
Admixed American	0.00833%	12,001
European (non-Finnish)	0.00593%	16,855
South Asian	0.0011%	91,082

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.Arg1476Ter
Coding: c.4426C>T
MANE Select: NM_001735
dbSNP: rs121909588
Type: single nucleotide variant
Location: chr9:120962749 (GRCh38)
Gene constraint: LOEUF 0.779 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.67 · 49 PDB
Residue 1476: a disulfide bond; a β-strand; a UniProt-annotated variant site (in c5d)

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

Disease context

C5-related disorders

Also linked: complement component 5 deficiency

Similar variants

C5 c.2257+1G>A Likely pathogenic ★★ same condition
C5 c.4679-2A>G Likely pathogenic ★★ same condition
C5 p.Gln19Ter Pathogenic ★★ same condition
C5 p.Glu1437Ter Pathogenic/Likely 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-arg1476ter (accessed [today's date]).

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