C1S p.Pro512=
c.1536G>A · VCV4536008
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 0.0022%, sas)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal. | ||
| Splicing | ||
| SpliceAI | Δ0.87 | acceptor gain · deltas |
|---|---|---|
| Pangolin | Δ0.62 | gain · loss 0.00 · agrees with SpliceAI · independent |
| Constraint at this position | ||
| Conservation | phyloP -8.4 | GERP -3.6 |
| Overall | ||
| CADD | 21.5 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0022%
South Asian · 2/91,076 alleles
Filtering AF
0.000365%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.000137%
Overall
0.000186%
3/1,614,042 alleles · very rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| South Asiangrpmax | 0.0022% | 45,538 |
| Admixed American | 0.00167% | 60,002 |
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.Pro512=
- Coding
- c.1536G>A
- MANE Select
- NM_001734
- Type
- single nucleotide variant
- Location
- chr12:7070120 (GRCh38)
- Gene constraint
- LOEUF 0.783 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 88.02 · 14 PDB
- Residue 512
- a disulfide bond; the peptidase s1 domain
Similar variants
- C1S p.Pro512Leu Uncertain significance ★ ⚠ 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-pro512 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown