Is C1S p.Ile187= (c.561T>A) pathogenic?

C1S p.Ile187= (c.561T>A) is classified Benign/Likely benign in C1S (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-04-20). Rare (popmax 0.862%, eas).

How common is C1S p.Ile187= (c.561T>A) in the general population?

C1S p.Ile187= (c.561T>A) is rare (popmax 0.862%, eas) (gnomAD).

C1S p.Ile187=

c.561T>A · rs143509101 · VCV1599334

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.862%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.9	GERP -3.7
Overall
CADD	2.758	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.862% East Asian · 387/44,882 alleles

Filtering AF 0.791% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.763%

Overall 0.0254% 410/1,614,094 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.862%	116
South Asian	0.0143%	7,006
Remaining individualsnot grpmax-eligible	0.0112%	8,929
Admixed American	0.00333%	30,005
European (non-Finnish)	8.47e-05%	1,179,980

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.Ile187=
Coding: c.561T>A
MANE Select: NM_001734
dbSNP: rs143509101
Type: single nucleotide variant
Location: chr12:7065143 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.02 · 14 PDB
Residue 187: a disulfide bond; the cub 2 domain; a β-strand

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

Similar variants

C1S p.Ile187Met 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-ile187 (accessed [today's date]).

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