Is C1S p.Gln71fs (c.211_212del) pathogenic?

C1S p.Gln71fs (c.211212del) is classified Pathogenic in C1S (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-22). Very rare (popmax 0.000137%).

How common is C1S p.Gln71fs (c.211_212del) in the general population?

C1S p.Gln71fs (c.211_212del) is very rare (popmax 0.000137%) (gnomAD).

C1S p.Gln71fs

c.211_212del · rs2539593557 · VCV2863263

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000137%)

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 3 of 12
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.1	GERP -0.32, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000137%

Overall 0.000137% 2/1,460,346 alleles · very rare

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: C1S
Protein: p.Gln71fs
Coding: c.211_212del
MANE Select: NM_001734
dbSNP: rs2539593557
Type: Deletion
Location: chr12:7062680 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.02 · 14 PDB
Residue 71: a disulfide bond; the cub 1 domain; a β-strand

Full C1S gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

C1S p.Gln71= Uncertain significance ★ same residue
C1S p.Ser115fs Pathogenic ★★ same type
C1S c.518-13_518-6del Benign/Likely benign ★★ same type
C1S c.6-10_6-9del Likely benign ★★ same type
C1S p.Arg481fs Pathogenic ★ same type
C1S p.Asn233fs Pathogenic ★ same type
C1S p.Asn27fs Pathogenic ★ same type
C1S p.Asn344fs 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/c1s-p-gln71fs (accessed [today's date]).

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