Is C6 p.Ser277fs (c.828del) pathogenic?

C6 p.Ser277fs (c.828del) is classified Pathogenic in C6 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-02-14). Very rare (popmax 0.00133%, afr); Associated with complement component 6 deficiency.

What condition is associated with C6 p.Ser277fs (c.828del)?

C6 p.Ser277fs (c.828del) is associated with complement component 6 deficiency (ClinVar).

How common is C6 p.Ser277fs (c.828del) in the general population?

C6 p.Ser277fs (c.828del) is very rare (popmax 0.00133%, afr) (gnomAD).

C6 p.Ser277fs

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.828del · rs372345940 · VCV12115

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

complement component 6 deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 7 of 18
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -12	GERP -3.5

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,930 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000616% 9/1,461,116 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0096%	10,412
African / African-Americangrpmax	0.00133%	74,930
European (non-Finnish)	0.00017%	589,717

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser277fs
Coding: c.828del
MANE Select: NM_000065
dbSNP: rs372345940
Type: Deletion
Location: chr5:41181458 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.72 · 11 PDB
Residue 277: a β-strand; 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.Gln274fs Pathogenic/Likely pathogenic ★★ same condition
C6 p.Gln380fs Pathogenic/Likely pathogenic ★★ same condition
C6 p.Gln779fs Pathogenic/Likely pathogenic ★★ same condition
C6 p.Cys837_Asp839delinsTer Likely pathogenic ★ same condition
C6 p.Trp90fs Likely pathogenic ★ same condition
C6 p.Ser277Asn Uncertain significance ★ ⚠ same residue
C6 p.Ser277= Likely benign ★ same residue
C6 p.Ile80fs 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-ser277fs (accessed [today's date]).

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