Is C1S p.Gln71= (c.213G>A) pathogenic?

C1S p.Gln71= (c.213G>A) is classified Uncertain significance in C1S (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-05). Very rare (popmax 0.000424%, nfe).

How common is C1S p.Gln71= (c.213G>A) in the general population?

C1S p.Gln71= (c.213G>A) is very rare (popmax 0.000424%, nfe) (gnomAD).

C1S p.Gln71=

c.213G>A · VCV3656957

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.82	donor loss · deltas
Pangolin	Δ0.69	loss · gain 0.53 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 0.8, phastCons 1
Overall
CADD	22.9	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,179,004 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000342% 5/1,460,212 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.Gln71=
Coding: c.213G>A
MANE Select: NM_001734
Type: single nucleotide variant
Location: chr12:7062682 (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.Gln71fs Pathogenic ★ same residue
C1S p.Arg523Ter Pathogenic ★★ same type
C1S c.1196-3C>T Uncertain significance ★★ same type
C1S c.717+5G>A Uncertain significance ★★ same type
C1S c.717+6T>A Uncertain significance ★★ same type
C1S p.Ala227Val Uncertain significance ★★ ⚠ same type
C1S p.Ala231Val Uncertain significance ★★ ⚠ same type
C1S p.Ala584Val Uncertain significance ★★ ⚠ 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-gln71 (accessed [today's date]).

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