Is C1S p.Arg686His (c.2057G>A) pathogenic?

C1S p.Arg686His (c.2057G>A) is classified Uncertain significance in C1S (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0839); Very rare (popmax 0.0061%, nfe); Associated with Inborn genetic diseases.

What condition is associated with C1S p.Arg686His (c.2057G>A)?

C1S p.Arg686His (c.2057G>A) is associated with Inborn genetic diseases (ClinVar).

How common is C1S p.Arg686His (c.2057G>A) in the general population?

C1S p.Arg686His (c.2057G>A) is very rare (popmax 0.0061%, nfe) (gnomAD).

What do computational predictors say about C1S p.Arg686His (c.2057G>A)?

AlphaMissense predicts likely benign (score 0.0839) — an in-silico prediction, not a clinical call.

C1S p.Arg686His

c.2057G>A · rs782484390 · VCV1525339

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0839 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0061%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0839	likely benign
REVEL	0.246	benign-leaning
SaProt	LLR -7.51	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 0.83	GERP -3.6
Regional constraint	o/e 0.79	unconstrained · MANE · 3,608 bp · p 1.1e-05 · regional, not allelic
Overall
CADD	8.265	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

Grpmax group 0.0061% European (non-Finnish) · 72/1,179,890 alleles

Filtering AF 0.00495% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00455%

Overall 0.00477% 77/1,613,592 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0061%	16,387
East Asian	0.00445%	22,448
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
Remaining individualsnot grpmax-eligible	0.0016%	62,454
African / African-American	0.00133%	74,924

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.Arg686His
Coding: c.2057G>A
MANE Select: NM_001734
dbSNP: rs782484390
Type: single nucleotide variant
Location: chr12:7070641 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.02 · 14 PDB

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.Arg686Leu Uncertain significance ★★ ⚠ same residue
C1S p.Arg686Cys 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

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-arg686his (accessed [today's date]).

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