Is C6 p.Gln111fs (c.331_334del) pathogenic?

C6 p.Gln111fs (c.331334del) is classified Likely pathogenic in C6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-02). Very rare (popmax 0.00273%); Associated with C6-related disorders.

What condition is associated with C6 p.Gln111fs (c.331_334del)?

C6 p.Gln111fs (c.331_334del) is associated with C6-related disorders (ClinVar).

How common is C6 p.Gln111fs (c.331_334del) in the general population?

C6 p.Gln111fs (c.331_334del) is very rare (popmax 0.00273%) (gnomAD).

C6 p.Gln111fs

c.331_334del · VCV4970250

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00273%)

Conditions

C6-related disorders

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 4 of 18
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Overall
CADD	34.0	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 0.00273%

Overall 0.00273% 44/1,613,640 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0656%	1,525
Remaining individualsnot grpmax-eligible	0.0032%	31,238

Finnish 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.Gln111fs
Coding: c.331_334del
MANE Select: NM_000065
Type: Microsatellite
Location: chr5:41199879 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.72 · 11 PDB
Residue 111: a disulfide bond; the tsp type-1 2 domain

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

Disease context

C6-related disorders

Similar variants

C6 p.Asp627fs Likely pathogenic ★★ same condition
C6 p.Ser813fs Pathogenic/Likely pathogenic ★★ same condition
C6 p.Gln268Ter Likely pathogenic ★ same condition
C6 c.-3G>A Likely benign same condition
C6 p.Arg289= Likely benign same condition
C6 p.Gln544fs Pathogenic/Likely pathogenic ★★ same type
C6 p.Val802_Phe803insTer Pathogenic/Likely pathogenic ★★ same type
C6 p.Cys543fs Likely pathogenic ★ 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/c6-p-gln111fs (accessed [today's date]).

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