Is C1S p.Pro389= (c.1167A>G) pathogenic?

C1S p.Pro389= (c.1167A>G) is classified Benign in C1S (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-04). Common (popmax 16.8%, afr) — too common for a highly-penetrant pathogenic allele.

C1S p.Pro389=

Q: How common is C1S p.Pro389= (c.1167A>G) in the general population?

C1S p.Pro389= (c.1167A>G) is common (popmax 16.8%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1167A>G · rs1143664 · VCV402440

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Common

common (popmax 16.8%, afr) — too common for a highly-penetrant pathogenic allele

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 -8	GERP -3.3
Overall
CADD	0.166	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 16.8% African / African-American · 12,586/74,988 alleles

Filtering AF 16.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 16.4%

Overall 7.81% 125,932/1,613,332 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	16.8%	6
Middle Eastern	16.5%	6
Ashkenazi Jewishnot grpmax-eligible	14.1%	7
Amishnot grpmax-eligible	10.6%	9
South Asian	8.86%	11
Remaining individualsnot grpmax-eligible	8.81%	11
European (non-Finnish)	7.32%	14
Finnishnot grpmax-eligible	6.61%	15
Admixed American	6.52%	15
East Asian	0.129%	774

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.Pro389=
Coding: c.1167A>G
MANE Select: NM_001734
dbSNP: rs1143664
Type: single nucleotide variant
Location: chr12:7067743 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.02 · 14 PDB
Residue 389: a turn; a disulfide bond; the sushi 2 domain

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

Similar variants

C1S p.Pro389Thr Uncertain significance ★★ ⚠ same residue
C1S p.Pro389Leu 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

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-pro389 (accessed [today's date]).

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