Is C1S p.Arg667Trp (c.1999C>T) pathogenic?

C1S p.Arg667Trp (c.1999C>T) is classified Uncertain significance in C1S (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-26). AlphaMissense: likely benign (0.1427); Very rare (popmax 0.00801%, afr).

How common is C1S p.Arg667Trp (c.1999C>T) in the general population?

C1S p.Arg667Trp (c.1999C>T) is very rare (popmax 0.00801%, afr) (gnomAD).

What do computational predictors say about C1S p.Arg667Trp (c.1999C>T)?

AlphaMissense predicts likely benign (score 0.1427) — an in-silico prediction, not a clinical call.

C1S p.Arg667Trp

c.1999C>T · rs377093428 · VCV1474892

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1427 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1427	likely benign
REVEL	0.357	indeterminate
SaProt	LLR -12.22	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -3.6
Regional constraint	o/e 0.79	unconstrained · MANE · 3,608 bp · p 1.1e-05 · regional, not allelic
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00801% African / African-American · 6/74,866 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.00198% 32/1,613,856 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00801%	12,478
East Asian	0.00668%	14,965
Admixed American	0.005%	19,993
South Asian	0.00439%	22,768
Remaining individualsnot grpmax-eligible	0.0016%	62,480
European (non-Finnish)	0.00127%	78,665

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.Arg667Trp
Coding: c.1999C>T
MANE Select: NM_001734
dbSNP: rs377093428
Type: single nucleotide variant
Location: chr12:7070583 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.02 · 14 PDB
Residue 667: a β-strand; the peptidase s1 domain

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

Similar variants

C1S p.Arg667= Likely benign ★★ same residue
C1S p.Arg667Gln Uncertain significance ★ ⚠ same residue
C1S p.Arg667Gly 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

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-arg667trp (accessed [today's date]).

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