Is C9 p.Arg139Cys (c.415C>T) pathogenic?

C9 p.Arg139Cys (c.415C>T) is classified Uncertain significance in C9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-10). AlphaMissense: likely pathogenic (0.7418); Ultra-rare (popmax 0.0466%, amr).

How common is C9 p.Arg139Cys (c.415C>T) in the general population?

C9 p.Arg139Cys (c.415C>T) is ultra-rare (popmax 0.0466%, amr) (gnomAD).

What do computational predictors say about C9 p.Arg139Cys (c.415C>T)?

AlphaMissense predicts likely pathogenic (score 0.7418) — an in-silico prediction, not a clinical call.

C9 p.Arg139Cys

c.415C>T · rs200646202 · VCV1441292

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7418 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0466%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7418	likely pathogenic
REVEL	0.188	benign-leaning
SaProt	LLR -7.30	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 0.31, phastCons 0.99
Regional constraint	o/e 1.11	unconstrained · MANE · 79 kb · p 0.0043 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0466% Admixed American · 28/60,024 alleles

Filtering AF 0.0331% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0286%

Overall 0.00626% 101/1,614,120 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0466%	2,144
East Asian	0.0111%	8,974
European (non-Finnish)	0.00534%	18,730
South Asian	0.00329%	30,358
Remaining individualsnot grpmax-eligible	0.0016%	62,512
African / African-American	0.00133%	75,022

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.Arg139Cys
Coding: c.415C>T
MANE Select: NM_001737
dbSNP: rs200646202
Type: single nucleotide variant
Location: chr5:39341207 (GRCh38)
Gene constraint: LOEUF 1.223 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.32 · 9 PDB
Residue 139: the macpf domain

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

Similar variants

C9 p.Arg139His Uncertain significance ★★ ⚠ same residue
C9 p.Arg139= Benign/Likely benign ★★ same residue
C9 p.Arg139fs Pathogenic ★ same residue
C9 c.871-2A>G Likely pathogenic ★★ same type
C9 p.Arg116Ter Pathogenic/Likely pathogenic ★★ same type
C9 p.Arg154Ter Pathogenic/Likely pathogenic ★★ same type
C9 p.Arg194Ter Pathogenic/Likely pathogenic ★★ same type
C9 p.Arg86Ter Pathogenic/Likely pathogenic ★★ same type

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-arg139cys (accessed [today's date]).

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