Is C9 p.Arg86Ter (c.256C>T) pathogenic?

C9 p.Arg86Ter (c.256C>T) is classified Pathogenic/Likely pathogenic in C9 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-29). Very rare (popmax 0.00666%, amr); Associated with C9-related disorders.

What condition is associated with C9 p.Arg86Ter (c.256C>T)?

C9 p.Arg86Ter (c.256C>T) is associated with C9-related disorders (ClinVar).

How common is C9 p.Arg86Ter (c.256C>T) in the general population?

C9 p.Arg86Ter (c.256C>T) is very rare (popmax 0.00666%, amr) (gnomAD).

C9 p.Arg86Ter

c.256C>T · rs148881448 · VCV2057844

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00666%, amr)

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 3 of 11
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.6	GERP -3.3
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 0.00666% Admixed American · 4/60,022 alleles

Filtering AF 0.00315% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00279%

Overall 0.00812% 131/1,613,622 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.23%	435
Admixed Americangrpmax	0.00666%	15,006
Remaining individualsnot grpmax-eligible	0.0064%	15,622
African / African-American	0.00533%	18,759
European (non-Finnish)	0.00407%	24,573
South Asian	0.00329%	30,358

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg86Ter
Coding: c.256C>T
MANE Select: NM_001737
dbSNP: rs148881448
Type: single nucleotide variant
Location: chr5:39341628 (GRCh38)
Gene constraint: LOEUF 1.223 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.32 · 9 PDB
Residue 86: a disulfide bond; a β-strand; the tsp type-1 domain

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

Disease context

C9-related disorders

Similar variants

C9 p.Arg86Gln Uncertain significance ★ ⚠ same residue
C9 c.871-2A>G Likely pathogenic ★★ same condition
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 c.1241-2A>G Likely pathogenic ★ same condition
C9 c.1240+2T>C Conflicting classifications of pathogenicity ★ same condition
C9 p.Thr109Lys 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-arg86ter (accessed [today's date]).

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