Is C9 p.Cys54Ter (c.162C>A) pathogenic?

C9 p.Cys54Ter (c.162C>A) is classified Pathogenic/Likely pathogenic in C9 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-01). Rare (popmax 0.145%, nfe); Associated with C9-related disorders.

What condition is associated with C9 p.Cys54Ter (c.162C>A)?

C9 p.Cys54Ter (c.162C>A) is associated with C9-related disorders, complement component 9 deficiency, age related macular degeneration 15 (ClinVar).

How common is C9 p.Cys54Ter (c.162C>A) in the general population?

C9 p.Cys54Ter (c.162C>A) is rare (popmax 0.145%, nfe) (gnomAD).

C9 p.Cys54Ter

c.162C>A · rs34000044 · VCV17041

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

rare (popmax 0.145%, nfe)

Conditions

C9-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 2 of 11
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.82	GERP -1.6, phastCons 0.63
Overall
CADD	35.0	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 0.145% European (non-Finnish) · 1,679/1,158,890 alleles

Filtering AF 0.139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.137%

Overall 0.119% 1,893/1,591,052 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.145%	690
Finnishnot grpmax-eligible	0.144%	696
Remaining individualsnot grpmax-eligible	0.0875%	1,143
Ashkenazi Jewishnot grpmax-eligible	0.0781%	1,281
Admixed American	0.0367%	2,727
African / African-American	0.0268%	3,727
Middle Eastern	0.0166%	6,030
South Asian	0.00221%	45,343

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.Cys54Ter
Coding: c.162C>A
MANE Select: NM_001737
dbSNP: rs34000044
Type: single nucleotide variant
Location: chr5:39342112 (GRCh38)
Gene constraint: LOEUF 1.223 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.32 · 9 PDB
Residue 54: a disulfide bond; an α-helix; the tsp type-1 domain

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

Disease context

C9-related disorders

Also linked: complement component 9 deficiency age related macular degeneration 15

Similar variants

C9 p.Cys54= Likely benign ★★ same residue
C9 p.Cys54Tyr Uncertain significance ★ ⚠ same residue
C9 c.871-2A>G Likely pathogenic ★★ same condition
C9 p.Arg116Ter Pathogenic/Likely pathogenic ★★ same condition
C9 p.Arg154Ter Pathogenic/Likely pathogenic ★★ same condition
C9 p.Arg194Ter Pathogenic/Likely pathogenic ★★ same condition
C9 p.Arg86Ter Pathogenic/Likely pathogenic ★★ same condition
C9 p.Gly126Arg 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/c9-p-cys54ter (accessed [today's date]).

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