Is C9 p.Arg154Ter (c.460C>T) pathogenic?

C9 p.Arg154Ter (c.460C>T) is classified Pathogenic/Likely pathogenic in C9 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-25). Ultra-rare (popmax 0.033%, mid); Associated with complement component 9 deficiency.

What condition is associated with C9 p.Arg154Ter (c.460C>T)?

C9 p.Arg154Ter (c.460C>T) is associated with complement component 9 deficiency (ClinVar).

How common is C9 p.Arg154Ter (c.460C>T) in the general population?

C9 p.Arg154Ter (c.460C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

C9 p.Arg154Ter

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.460C>T · rs144138616 · VCV1029525

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 0.033%, mid)

Conditions

complement component 9 deficiency

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 4 of 11
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 2.1, phastCons 0.68
Overall
CADD	37.0	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 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.0141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0112%

Overall 0.00297% 48/1,614,120 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
Admixed American	0.0233%	4,287
African / African-American	0.008%	12,504
East Asian	0.00446%	22,441
European (non-Finnish)	0.00186%	53,637
Remaining individualsnot grpmax-eligible	0.0016%	62,508
South Asian	0.0011%	91,068

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: C9
Protein: p.Arg154Ter
Coding: c.460C>T
MANE Select: NM_001737
dbSNP: rs144138616
Type: single nucleotide variant
Location: chr5:39341162 (GRCh38)
Gene constraint: LOEUF 1.223 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.32 · 9 PDB
Residue 154: the macpf domain; a disulfide bond; a turn

Full C9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

complement component 9 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

C9 p.Arg154Gln Uncertain significance ★★ ⚠ same residue
C9 p.Arg154Pro Uncertain significance ★★ ⚠ same residue
C9 p.Arg116Ter Pathogenic/Likely pathogenic ★★ same condition
C9 p.Arg194Ter Pathogenic/Likely pathogenic ★★ same condition
C9 p.Cys54Ter Pathogenic/Likely pathogenic ★★ same condition
C9 p.Gly126Arg Uncertain significance ★★ same condition
C9 p.Ala325Val Likely benign ★★ same condition
C9 p.Met45Leu 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/c9-p-arg154ter (accessed [today's date]).

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