Is C9 p.Arg118Trp (c.352C>T) pathogenic?

C9 p.Arg118Trp (c.352C>T) is classified Uncertain significance in C9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-24). AlphaMissense: likely benign (0.2003); Ultra-rare (popmax 0.0255%, nfe).

How common is C9 p.Arg118Trp (c.352C>T) in the general population?

C9 p.Arg118Trp (c.352C>T) is ultra-rare (popmax 0.0255%, nfe) (gnomAD).

What do computational predictors say about C9 p.Arg118Trp (c.352C>T)?

AlphaMissense predicts likely benign (score 0.2003) — an in-silico prediction, not a clinical call.

C9 p.Arg118Trp

c.352C>T · rs147701327 · VCV1040151

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2003 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0255%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2003	likely benign
REVEL	0.222	benign-leaning
SaProt	LLR -10.03	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 0.99, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 79 kb · p 0.0043 · regional, not allelic
Overall
CADD	23.2	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 0.0255% European (non-Finnish) · 301/1,180,014 alleles

Filtering AF 0.0231% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0222%

Overall 0.0197% 318/1,613,986 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0255%	3,920
Remaining individualsnot grpmax-eligible	0.0112%	8,926
African / African-American	0.00534%	18,729
Admixed American	0.005%	19,999
Finnishnot grpmax-eligible	0.00312%	32,005
East Asian	0.00223%	44,884

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.Arg118Trp
Coding: c.352C>T
MANE Select: NM_001737
dbSNP: rs147701327
Type: single nucleotide variant
Location: chr5:39341270 (GRCh38)
Gene constraint: LOEUF 1.223 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.32 · 9 PDB
Residue 118: a disulfide bond; a β-strand; the ldl-receptor class a domain

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

Similar variants

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
C9 p.Cys54Ter Pathogenic/Likely pathogenic ★★ same type
C9 c.1240+5G>T Uncertain significance ★★ same type
C9 p.Ala497Val Uncertain significance ★★ ⚠ 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-arg118trp (accessed [today's date]).

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