Is C3 p.Arg735Trp (c.2203C>T) pathogenic?

C3 p.Arg735Trp (c.2203C>T) is classified Conflicting classifications of pathogenicity in C3 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.3176); Rare (popmax 0.314%, mid); Associated with atypical hemolytic-uremic syndrome.

What condition is associated with C3 p.Arg735Trp (c.2203C>T)?

C3 p.Arg735Trp (c.2203C>T) is associated with atypical hemolytic-uremic syndrome, age related macular degeneration 9, atypical hemolytic-uremic syndrome with C3 anomaly (ClinVar).

How common is C3 p.Arg735Trp (c.2203C>T) in the general population?

C3 p.Arg735Trp (c.2203C>T) is rare (popmax 0.314%, mid) (gnomAD).

How is Atypical hemolytic uremic syndrome inherited?

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

What do computational predictors say about C3 p.Arg735Trp (c.2203C>T)?

AlphaMissense predicts likely benign (score 0.3176) — an in-silico prediction, not a clinical call.

C3 p.Arg735Trp

c.2203C>T · rs117793540 · VCV330310

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.3176 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.314%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

atypical hemolytic-uremic syndrome

Computational evidence

Protein change
AlphaMissense	0.3176	likely benign
REVEL	0.345	indeterminate
SaProt	LLR -9.40	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP -0.44, phastCons 0.99
Regional constraint	o/e 0.74	unconstrained · MANE · 35 kb · p 3.5e-28 · regional, not allelic
Overall
CADD	18.97	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 0.314% Middle Eastern · 19/6,060 alleles

Filtering AF 0.244% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.241%

Overall 0.233% 3,760/1,613,164 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.27%	79
Middle Easterngrpmax	0.314%	319
Remaining individualsnot grpmax-eligible	0.29%	345
European (non-Finnish)	0.251%	398
Admixed American	0.225%	444
Finnishnot grpmax-eligible	0.0613%	1,630
African / African-American	0.0494%	2,024
South Asian	0.00879%	11,383

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: C3
Protein: p.Arg735Trp
Coding: c.2203C>T
MANE Select: NM_000064
dbSNP: rs117793540
Type: single nucleotide variant
Location: chr19:6707118 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 735: an α-helix; a disulfide bond; a UniProt-annotated variant site (in ahus5)

Full C3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

atypical hemolytic-uremic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: age related macular degeneration 9 atypical hemolytic-uremic syndrome with C3 anomaly complement component 3 deficiency C3 glomerulonephritis

For Atypical hemolytic uremic syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: All ages
Prevalence: 1-9 / 1 000 000 (United States)

Similar variants

C3 p.Arg735Gln Uncertain significance ★★ ⚠ same residue
C3 c.1003+1G>A Pathogenic/Likely pathogenic ★★ same condition
C3 c.2863+1G>T Likely pathogenic ★★ same condition
C3 c.4030-2A>G Likely pathogenic ★★ same condition
C3 p.Arg161Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
C3 p.Arg592Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
C3 p.Arg592Trp Likely pathogenic ★★ ⚠ same condition
C3 p.Arg764Ter Pathogenic/Likely pathogenic ★★ 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/c3-p-arg735trp (accessed [today's date]).

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