Is C1S p.Arg207Trp (c.619C>T) pathogenic?

C1S p.Arg207Trp (c.619C>T) is classified Uncertain significance in C1S (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-12-06). AlphaMissense: likely benign (0.0897); Very rare (popmax 0.00666%, afr).

How common is C1S p.Arg207Trp (c.619C>T) in the general population?

C1S p.Arg207Trp (c.619C>T) is very rare (popmax 0.00666%, afr) (gnomAD).

What do computational predictors say about C1S p.Arg207Trp (c.619C>T)?

AlphaMissense predicts likely benign (score 0.0897) — an in-silico prediction, not a clinical call.

C1S p.Arg207Trp

c.619C>T · rs781922815 · VCV1501620

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0897 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00666%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0897	likely benign
REVEL	0.129	moderately benign-leaning
SaProt	LLR -12.78	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.76	GERP -1.8
Regional constraint	o/e 0.98	unconstrained · MANE · 4,638 bp · p 0.66 · regional, not allelic
Overall
CADD	19.86	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 0.00666% African / African-American · 5/75,020 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.00118% 19/1,613,838 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00666%	15,004
East Asian	0.00223%	44,880
Remaining individualsnot grpmax-eligible	0.0016%	62,500
South Asian	0.0011%	91,070
European (non-Finnish)	0.000932%	107,250

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.Arg207Trp
Coding: c.619C>T
MANE Select: NM_001734
dbSNP: rs781922815
Type: single nucleotide variant
Location: chr12:7065201 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.02 · 14 PDB
Residue 207: 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.Arg207Gln 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-arg207trp (accessed [today's date]).

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