Is C2 p.Glu433Gly (c.1298A>G) pathogenic?

C2 p.Glu433Gly (c.1298A>G) is classified Uncertain significance in C2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-27). AlphaMissense: likely pathogenic (0.6764); Absent from gnomAD v4.1; Associated with complement component 2 deficiency.

What condition is associated with C2 p.Glu433Gly (c.1298A>G)?

C2 p.Glu433Gly (c.1298A>G) is associated with complement component 2 deficiency (ClinVar).

How common is C2 p.Glu433Gly (c.1298A>G) in the general population?

C2 p.Glu433Gly (c.1298A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about C2 p.Glu433Gly (c.1298A>G)?

AlphaMissense predicts likely pathogenic (score 0.6764) — an in-silico prediction, not a clinical call.

C2 p.Glu433Gly

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.1298A>G · VCV3906892

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6764 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

complement component 2 deficiency

Computational evidence

Protein change
AlphaMissense	0.6764	likely pathogenic
REVEL	0.805	moderately pathogenic-leaning
SaProt	LLR -7.69	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 9.4	GERP 1.8, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 18 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	28.4	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

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: C2
Protein: p.Glu433Gly
Coding: c.1298A>G
Type: single nucleotide variant
Location: chr6:31943037 (GRCh38)

Full C2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

complement component 2 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

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/c2-p-glu433gly (accessed [today's date]).

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