Is C2 p.Met280fs (c.839_849del) pathogenic?

C2 p.Met280fs (c.839849del) is classified Likely pathogenic in C2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-05-03). Absent from gnomAD; Associated with complement component 2 deficiency.

What condition is associated with C2 p.Met280fs (c.839_849del)?

C2 p.Met280fs (c.839_849del) is associated with complement component 2 deficiency (ClinVar).

How common is C2 p.Met280fs (c.839_849del) in the general population?

C2 p.Met280fs (c.839_849del) is absent from gnomAD (gnomAD).

C2 p.Met280fs

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.839_849del · rs1770220135 · VCV915386

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

complement component 2 deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 6 of 18
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.1	GERP 1.7, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: C2
Protein: p.Met280fs
Coding: c.839_849del
MANE Select: NM_000063
dbSNP: rs1770220135
Type: Deletion
Location: chr6:31934289 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 14 PDB
Residue 280: the vwfa domain; an α-helix

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 c.841_849+19del Pathogenic/Likely pathogenic ★★ same condition
C2 c.1567+22_1567+43del Benign/Likely benign ★★ same condition
C2 p.Pro92fs Pathogenic ★ same condition
C2 p.Met280Ile Uncertain significance ★ ⚠ same residue
C2 p.Met280Val Uncertain significance ★ ⚠ same residue
C2 p.Lys610fs Likely pathogenic ★★ same condition
C2 p.Arg129His Uncertain significance ★★ same condition
C2 p.Arg734Leu 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-met280fs (accessed [today's date]).

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