Is C3 p.Asp1222Ala (c.3665A>C) pathogenic?

C3 p.Asp1222Ala (c.3665A>C) is classified Uncertain significance in C3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-30). AlphaMissense: likely benign (0.2831); Absent from gnomAD v4.1; Associated with complement component 3 deficiency.

What condition is associated with C3 p.Asp1222Ala (c.3665A>C)?

C3 p.Asp1222Ala (c.3665A>C) is associated with complement component 3 deficiency, C3 glomerulonephritis, atypical hemolytic-uremic syndrome (ClinVar).

How common is C3 p.Asp1222Ala (c.3665A>C) in the general population?

C3 p.Asp1222Ala (c.3665A>C) is absent from gnomAD v4.1 (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.Asp1222Ala (c.3665A>C)?

AlphaMissense predicts likely benign (score 0.2831) — an in-silico prediction, not a clinical call.

C3 p.Asp1222Ala

c.3665A>C · VCV4280222

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2831 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

complement component 3 deficiency

Computational evidence

Protein change
AlphaMissense	0.2831	likely benign
REVEL	0.139	moderately benign-leaning
SaProt	LLR -9.62	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 6.1	GERP 1.7, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 35 kb · p 3.5e-28 · regional, not allelic
Overall
CADD	24.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: C3
Protein: p.Asp1222Ala
Coding: c.3665A>C
MANE Select: NM_000064
Type: single nucleotide variant
Location: chr19:6686269 (GRCh38)
Gene constraint: LOEUF 0.541 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84 · 80 PDB
Residue 1222: 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: C3 glomerulonephritis atypical hemolytic-uremic syndrome

For Complement component 3 deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

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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
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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-asp1222ala (accessed [today's date]).

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