Is C9 p.Arg183Trp (c.547C>T) pathogenic?

C9 p.Arg183Trp (c.547C>T) is classified Likely benign in C9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-17). AlphaMissense: ambiguous (0.4362); Rare (popmax 0.244%, sas).

How common is C9 p.Arg183Trp (c.547C>T) in the general population?

C9 p.Arg183Trp (c.547C>T) is rare (popmax 0.244%, sas) (gnomAD).

What do computational predictors say about C9 p.Arg183Trp (c.547C>T)?

AlphaMissense predicts ambiguous (score 0.4362) — an in-silico prediction, not a clinical call.

C9 p.Arg183Trp

c.547C>T · rs369854518 · VCV1664771

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4362 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.244%, sas)

Computational evidence

Protein change
AlphaMissense	0.4362	ambiguous
REVEL	0.393	indeterminate
SaProt	LLR -9.38	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP -1.6, phastCons 0.99
Regional constraint	o/e 1.11	unconstrained · MANE · 79 kb · p 0.0043 · regional, not allelic
Overall
CADD	22.6	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 0.244% South Asian · 222/91,046 alleles

Filtering AF 0.217% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.207%

Overall 0.018% 290/1,612,944 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.244%	410
East Asian	0.049%	2,039
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0128%	7,807
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,799
African / African-American	0.00667%	15,000
Admixed American	0.005%	20,004
European (non-Finnish)	0.00229%	43,666

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.Arg183Trp
Coding: c.547C>T
MANE Select: NM_001737
dbSNP: rs369854518
Type: single nucleotide variant
Location: chr5:39331744 (GRCh38)
Gene constraint: LOEUF 1.223 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.32 · 9 PDB
Residue 183: the macpf domain; a β-strand

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-arg183trp (accessed [today's date]).

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