Is C2 p.Asn467His (c.1399A>C) pathogenic?

C2 p.Asn467His (c.1399A>C) is classified Uncertain significance in C2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-05-21). AlphaMissense: ambiguous (0.5435); Very rare (popmax 8.47e-05%, nfe); Associated with complement component 2 deficiency.

What condition is associated with C2 p.Asn467His (c.1399A>C)?

C2 p.Asn467His (c.1399A>C) is associated with complement component 2 deficiency (ClinVar).

How common is C2 p.Asn467His (c.1399A>C) in the general population?

C2 p.Asn467His (c.1399A>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about C2 p.Asn467His (c.1399A>C)?

AlphaMissense predicts ambiguous (score 0.5435) — an in-silico prediction, not a clinical call.

C2 p.Asn467His

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.1399A>C · rs1771039921 · VCV973621

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5435 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

complement component 2 deficiency

Computational evidence

Protein change
AlphaMissense	0.5435	ambiguous
REVEL	0.291	indeterminate
SaProt	LLR -4.90	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 18 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	25.7	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 8.47e-05% European (non-Finnish) · 1/1,180,014 alleles

Overall 6.85e-05% 1/1,460,764 alleles · very rare

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: C2
Protein: p.Asn467His
Coding: c.1399A>C
MANE Select: NM_000063
dbSNP: rs1771039921
Type: single nucleotide variant
Location: chr6:31943263 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 14 PDB
Residue 467: a disulfide bond; the peptidase s1 domain

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

Similar variants

C2 p.Arg129His Uncertain significance ★★ ⚠ same condition
C2 p.Arg734Leu Uncertain significance ★★ ⚠ same condition
C2 p.Asp390Ala Uncertain significance ★★ ⚠ same condition
C2 p.Asp661Asn Uncertain significance ★★ ⚠ same condition
C2 p.Lys572Asn Uncertain significance ★★ ⚠ same condition
C2 p.Phe273= Uncertain significance ★★ same condition
C2 p.Phe95Val Uncertain significance ★★ ⚠ same condition
C2 p.Ser250Cys Uncertain significance ★★ ⚠ 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/c2-p-asn467his (accessed [today's date]).

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