Is C2 p.Pro92fs (c.275_276del) pathogenic?

C2 p.Pro92fs (c.275276del) is classified Pathogenic in C2 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-09-28). Very rare (popmax 0.00169%, nfe); Associated with complement component 2 deficiency.

What condition is associated with C2 p.Pro92fs (c.275_276del)?

C2 p.Pro92fs (c.275_276del) is associated with complement component 2 deficiency (ClinVar).

How common is C2 p.Pro92fs (c.275_276del) in the general population?

C2 p.Pro92fs (c.275_276del) is very rare (popmax 0.00169%, nfe) (gnomAD).

C2 p.Pro92fs

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.275_276del · rs770780241 · VCV2054147

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00169%, nfe)

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 3 of 18
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00169% European (non-Finnish) · 20/1,180,056 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00155% 25/1,614,132 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00312%	32,020
European (non-Finnish)grpmax	0.00169%	59,003
Admixed American	0.00167%	60,008
Remaining individualsnot grpmax-eligible	0.0016%	62,484
South Asian	0.0011%	91,090

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro92fs
Coding: c.275_276del
MANE Select: NM_000063
dbSNP: rs770780241
Type: Deletion
Location: chr6:31928750 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 14 PDB
Residue 92: a disulfide bond; the sushi 2 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 c.841_849+19del Pathogenic/Likely pathogenic ★★ same condition
C2 c.1567+22_1567+43del Benign/Likely benign ★★ same condition
C2 p.Met280fs Likely pathogenic ★ same condition
C2 p.Lys610fs Likely pathogenic ★★ same condition
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

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-pro92fs (accessed [today's date]).

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