Is C1S p.Arg245Trp (c.733C>T) pathogenic?

C1S p.Arg245Trp (c.733C>T) is classified Uncertain significance in C1S (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-22). AlphaMissense: likely benign (0.117); Ultra-rare (popmax 0.033%, mid); Associated with complement component C1s deficiency.

What condition is associated with C1S p.Arg245Trp (c.733C>T)?

C1S p.Arg245Trp (c.733C>T) is associated with complement component C1s deficiency (ClinVar).

How common is C1S p.Arg245Trp (c.733C>T) in the general population?

C1S p.Arg245Trp (c.733C>T) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about C1S p.Arg245Trp (c.733C>T)?

AlphaMissense predicts likely benign (score 0.117) — an in-silico prediction, not a clinical call.

C1S p.Arg245Trp

Q: How is Immunodeficiency due to a classical component pathway complement deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.733C>T · rs147971272 · VCV830030

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.117 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

complement component C1s deficiency

Computational evidence

Protein change
AlphaMissense	0.117	likely benign
REVEL	0.108	moderately benign-leaning
SaProt	LLR -12.68	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	Δ0.20	acceptor loss, 15 bp away · masked 0 · deltas
Pangolin	Δ0.35	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.41	GERP 1.8
Regional constraint	o/e 0.98	unconstrained · MANE · 4,638 bp · p 0.66 · regional, not allelic
Overall
CADD	22.5	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 0.033% Middle Eastern · 2/6,058 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.00322% 52/1,612,574 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,029
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,803
East Asian	0.00668%	14,961
Admixed American	0.00333%	29,989
Remaining individualsnot grpmax-eligible	0.0032%	31,228
European (non-Finnish)	0.00314%	31,884
African / African-American	0.00271%	36,950
South Asian	0.0022%	45,532

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.Arg245Trp
Coding: c.733C>T
MANE Select: NM_001734
dbSNP: rs147971272
Type: single nucleotide variant
Location: chr12:7065832 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.02 · 14 PDB
Residue 245: a disulfide bond; the cub 2 domain; a β-strand

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

Disease context

complement component C1s deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Immunodeficiency due to a classical component pathway complement deficiency (Orphanet):

Inheritance: Autosomal recessive

Similar variants

C1S p.Arg245= Likely benign ★★ same residue
C1S p.Arg245Gly Uncertain significance ★ ⚠ same residue
C1S p.Arg523Ter Pathogenic ★★ same condition
C1S p.Arg331Cys Uncertain significance ★★ ⚠ same condition
C1S p.Arg534Trp Uncertain significance ★★ ⚠ same condition
C1S p.Gly172Arg Uncertain significance ★★ ⚠ same condition
C1S p.Ser380Phe Uncertain significance ★★ ⚠ same condition
C1S p.Leu208= Likely benign ★★ 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-arg245trp (accessed [today's date]).

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