Is C6 p.Arg606Ter (c.1816C>T) pathogenic?

C6 p.Arg606Ter (c.1816C>T) is classified Pathogenic in C6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-29). Ultra-rare (popmax 0.049%, eas); Associated with complement component 6 deficiency.

What condition is associated with C6 p.Arg606Ter (c.1816C>T)?

C6 p.Arg606Ter (c.1816C>T) is associated with complement component 6 deficiency (ClinVar).

How common is C6 p.Arg606Ter (c.1816C>T) in the general population?

C6 p.Arg606Ter (c.1816C>T) is ultra-rare (popmax 0.049%, eas) (gnomAD).

C6 p.Arg606Ter

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.1816C>T · rs191386155 · VCV2906086

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.049%, eas)

Conditions

complement component 6 deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 12 of 18
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.027	GERP -2.4
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.049% East Asian · 22/44,860 alleles

Filtering AF 0.0332% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0279%

Overall 0.0031% 50/1,613,530 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.049%	2,039
European (non-Finnish)	0.00229%	43,693
Remaining individualsnot grpmax-eligible	0.0016%	62,490

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.Arg606Ter
Coding: c.1816C>T
MANE Select: NM_000065
dbSNP: rs191386155
Type: single nucleotide variant
Location: chr5:41159122 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.72 · 11 PDB
Residue 606: a β-strand; a disulfide bond; the tsp type-1 3 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.Arg606Gln Uncertain significance ★ ⚠ same residue
C6 p.Arg606= Likely benign ★ same residue
C6 p.Arg596Ter Pathogenic/Likely pathogenic ★★ same condition
C6 p.Cys218Ter Pathogenic/Likely pathogenic ★★ same condition
C6 p.Tyr683Ter Pathogenic/Likely pathogenic ★★ same condition
C6 p.Arg407Cys Uncertain significance ★★ ⚠ same condition
C6 p.Arg48Lys Uncertain significance ★★ ⚠ same condition
C6 p.Arg701Trp 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-arg606ter (accessed [today's date]).

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