Is C3 p.Arg736Gln (c.2207G>A) pathogenic?

C3 p.Arg736Gln (c.2207G>A) is classified Conflicting classifications of pathogenicity in C3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-21). AlphaMissense: likely benign (0.0721); Ultra-rare (popmax 0.0469%, eas); Associated with complement component 3 deficiency.

What condition is associated with C3 p.Arg736Gln (c.2207G>A)?

C3 p.Arg736Gln (c.2207G>A) is associated with complement component 3 deficiency, age related macular degeneration 9, atypical hemolytic-uremic syndrome with C3 anomaly (ClinVar).

How common is C3 p.Arg736Gln (c.2207G>A) in the general population?

C3 p.Arg736Gln (c.2207G>A) is ultra-rare (popmax 0.0469%, eas) (gnomAD).

How is Complement component 3 deficiency inherited?

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

What do computational predictors say about C3 p.Arg736Gln (c.2207G>A)?

AlphaMissense predicts likely benign (score 0.0721) — an in-silico prediction, not a clinical call.

C3 p.Arg736Gln

c.2207G>A · rs578116271 · VCV892833

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0721 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0469%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

complement component 3 deficiency

Computational evidence

Protein change
AlphaMissense	0.0721	likely benign
REVEL	0.013	strongly benign-leaning
SaProt	LLR -6.10	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 -5.2	GERP -3.5
Regional constraint	o/e 0.74	unconstrained · MANE · 35 kb · p 3.5e-28 · regional, not allelic
Overall
CADD	0.688	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 0.0469% East Asian · 21/44,818 alleles

Filtering AF 0.0313% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0263%

Overall 0.00483% 78/1,613,238 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0469%	2,134
European (non-Finnish)	0.00458%	21,849
Admixed American	0.00167%	60,004
Remaining individualsnot grpmax-eligible	0.0016%	62,488
South Asian	0.0011%	91,062

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.Arg736Gln
Coding: c.2207G>A
MANE Select: NM_000064
dbSNP: rs578116271
Type: single nucleotide variant
Location: chr19:6707114 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 736: an α-helix; a disulfide bond

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

Disease context

complement component 3 deficiency — 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

For Complement component 3 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

C3 p.Arg736= Likely benign ★ 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-arg736gln (accessed [today's date]).

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