Is C1S p.Pro293Arg (c.878C>G) pathogenic?

C1S p.Pro293Arg (c.878C>G) is classified Uncertain significance in C1S (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-19). AlphaMissense: likely benign (0.125); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with C1S p.Pro293Arg (c.878C>G)?

C1S p.Pro293Arg (c.878C>G) is associated with Inborn genetic diseases (ClinVar).

How common is C1S p.Pro293Arg (c.878C>G) in the general population?

C1S p.Pro293Arg (c.878C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about C1S p.Pro293Arg (c.878C>G)?

AlphaMissense predicts likely benign (score 0.125) — an in-silico prediction, not a clinical call.

C1S p.Pro293Arg

c.878C>G · rs2539601351 · VCV3135832

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.125 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.125	likely benign
REVEL	0.276	benign-leaning
SaProt	LLR -7.79	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.7, phastCons 0.28
Regional constraint	o/e 0.98	unconstrained · MANE · 4,638 bp · p 0.66 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: C1S
Protein: p.Pro293Arg
Coding: c.878C>G
MANE Select: NM_001734
dbSNP: rs2539601351
Type: single nucleotide variant
Location: chr12:7066524 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.02 · 14 PDB
Residue 293: the sushi 1 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

C1S p.Pro293Leu Uncertain significance ★ ⚠ same residue
C1S p.Ala227Val Uncertain significance ★★ ⚠ same condition
C1S p.Ala231Val Uncertain significance ★★ ⚠ same condition
C1S p.Ala649Thr Uncertain significance ★★ ⚠ same condition
C1S p.Arg207Gln Uncertain significance ★★ ⚠ same condition
C1S p.Arg286Cys Uncertain significance ★★ ⚠ same condition
C1S p.Arg481Gly Uncertain significance ★★ ⚠ same condition
C1S p.Arg496Gln Uncertain significance ★★ ⚠ same condition

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-pro293arg (accessed [today's date]).

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