Is C9 p.Arg63Cys (c.187C>T) pathogenic?

C9 p.Arg63Cys (c.187C>T) is classified Uncertain significance in C9 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-16). AlphaMissense: likely pathogenic (0.8418); Ultra-rare (popmax 0.0187%, sas).

How common is C9 p.Arg63Cys (c.187C>T) in the general population?

C9 p.Arg63Cys (c.187C>T) is ultra-rare (popmax 0.0187%, sas) (gnomAD).

What do computational predictors say about C9 p.Arg63Cys (c.187C>T)?

AlphaMissense predicts likely pathogenic (score 0.8418) — an in-silico prediction, not a clinical call.

C9 p.Arg63Cys

c.187C>T · rs749534250 · VCV1511211

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8418 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8418	likely pathogenic
REVEL	0.811	moderately pathogenic-leaning
SaProt	LLR -14.15	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.59 · evaluated, not missing
Constraint at this position
Conservation	phyloP 8.5	GERP 1.3, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 79 kb · p 0.0043 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0187% South Asian · 17/91,076 alleles

Filtering AF 0.0118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00976%

Overall 0.00167% 27/1,613,754 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0187%	5,357
Admixed American	0.01%	9,999
European (non-Finnish)	0.000339%	294,951

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.Arg63Cys
Coding: c.187C>T
MANE Select: NM_001737
dbSNP: rs749534250
Type: single nucleotide variant
Location: chr5:39341697 (GRCh38)
Gene constraint: LOEUF 1.223 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.32 · 9 PDB
Residue 63: 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

Similar variants

C9 p.Arg63His Uncertain significance ★★ ⚠ 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
C9 p.Cys54Ter Pathogenic/Likely pathogenic ★★ same type
C9 c.1240+5G>T 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-arg63cys (accessed [today's date]).

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