Is C6 p.Arg407Cys (c.1219C>T) pathogenic?

C6 p.Arg407Cys (c.1219C>T) is classified Uncertain significance in C6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-08-25). AlphaMissense: ambiguous (0.4355); Ultra-rare (popmax 0.0132%, sas); Associated with complement component 6 deficiency.

What condition is associated with C6 p.Arg407Cys (c.1219C>T)?

C6 p.Arg407Cys (c.1219C>T) is associated with complement component 6 deficiency (ClinVar).

How common is C6 p.Arg407Cys (c.1219C>T) in the general population?

C6 p.Arg407Cys (c.1219C>T) is ultra-rare (popmax 0.0132%, sas) (gnomAD).

What do computational predictors say about C6 p.Arg407Cys (c.1219C>T)?

AlphaMissense predicts ambiguous (score 0.4355) — an in-silico prediction, not a clinical call.

C6 p.Arg407Cys

Q: How is Immunodeficiency due to a late component of complement deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1219C>T · rs147449601 · VCV1374116

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4355 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0132%, sas)

Conditions

complement component 6 deficiency

Computational evidence

Protein change
AlphaMissense	0.4355	ambiguous
REVEL	0.508	indeterminate
SaProt	LLR -11.85	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.8	GERP 0.37, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 60 kb · p 0.0034 · regional, not allelic
Overall
CADD	23.1	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 0.0132% South Asian · 12/91,058 alleles

Filtering AF 0.00751% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00593%

Overall 0.00167% 27/1,613,274 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0132%	7,588
East Asian	0.00669%	14,945
Admixed American	0.005%	19,986
European (non-Finnish)	0.000763%	131,046

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: C6
Protein: p.Arg407Cys
Coding: c.1219C>T
MANE Select: NM_000065
dbSNP: rs147449601
Type: single nucleotide variant
Location: chr5:41172297 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.72 · 11 PDB
Residue 407: an α-helix; a disulfide bond; the macpf domain

Full C6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

complement component 6 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Immunodeficiency due to a late component of complement deficiency (Orphanet):

Inheritance: Autosomal recessive

Similar variants

C6 p.Arg407= Likely benign ★ same residue
C6 p.Arg596Ter Pathogenic/Likely pathogenic ★★ same condition
C6 p.Arg606Ter Pathogenic ★★ same condition
C6 p.Cys218Ter Pathogenic/Likely pathogenic ★★ same condition
C6 p.Tyr683Ter Pathogenic/Likely pathogenic ★★ same condition
C6 p.Arg48Lys Uncertain significance ★★ ⚠ same condition
C6 p.Arg701Trp Uncertain significance ★★ ⚠ same condition
C6 p.Asp667His 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/c6-p-arg407cys (accessed [today's date]).

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