Is C6 p.Tyr451Ter (c.1352dup) pathogenic?

C6 p.Tyr451Ter (c.1352dup) is classified Pathogenic/Likely pathogenic in C6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-09). Rare (popmax 0.168%, sas); Associated with complement component 6 deficiency.

What condition is associated with C6 p.Tyr451Ter (c.1352dup)?

C6 p.Tyr451Ter (c.1352dup) is associated with complement component 6 deficiency (ClinVar).

How common is C6 p.Tyr451Ter (c.1352dup) in the general population?

C6 p.Tyr451Ter (c.1352dup) is rare (popmax 0.168%, sas) (gnomAD).

C6 p.Tyr451Ter

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.1352dup · rs779825789 · VCV2894375

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

rare (popmax 0.168%, sas)

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 10 of 18
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -3	GERP -3.8
Overall
CADD	27.4	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 0.168% South Asian · 153/91,082 alleles

Filtering AF 0.146% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.138%

Overall 0.00973% 157/1,613,710 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.168%	595
Middle Eastern	0.0165%	6,058
Remaining individualsnot grpmax-eligible	0.0048%	20,828

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.Tyr451Ter
Coding: c.1352dup
MANE Select: NM_000065
dbSNP: rs779825789
Type: Duplication
Location: chr5:41161798 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.72 · 11 PDB
Residue 451: an α-helix; 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.Tyr285fs Likely pathogenic ★ same condition
C6 p.Tyr451= 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.Gln274fs Pathogenic/Likely pathogenic ★★ same condition
C6 p.Gln380fs Pathogenic/Likely pathogenic ★★ same condition
C6 p.Gln544fs Pathogenic/Likely pathogenic ★★ 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-tyr451ter (accessed [today's date]).

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