Is C2 p.Pro751= (c.2253C>T) pathogenic?

C2 p.Pro751= (c.2253C>T) is classified Conflicting classifications of pathogenicity in C2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-19). Ultra-rare (popmax 0.0217%, amr); Associated with complement component 2 deficiency.

What condition is associated with C2 p.Pro751= (c.2253C>T)?

C2 p.Pro751= (c.2253C>T) is associated with complement component 2 deficiency, age related macular degeneration 14 (ClinVar).

How common is C2 p.Pro751= (c.2253C>T) in the general population?

C2 p.Pro751= (c.2253C>T) is ultra-rare (popmax 0.0217%, amr) (gnomAD).

C2 p.Pro751=

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.2253C>T · rs771797450 · VCV356261

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, amr)

Conditions

complement component 2 deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.531	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.2	GERP -4.1
Overall
CADD	4.186	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0217% Admixed American · 13/59,992 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0101%

Overall 0.00577% 93/1,612,786 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.111%	897
Admixed Americangrpmax	0.0217%	4,615
Remaining individualsnot grpmax-eligible	0.0128%	7,808
European (non-Finnish)	0.00314%	31,891
Finnishnot grpmax-eligible	0.00159%	62,858
South Asian	0.0011%	91,076

Ashkenazi Jewish 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.Pro751=
Coding: c.2253C>T
MANE Select: NM_000063
dbSNP: rs771797450
Type: single nucleotide variant
Location: chr6:31945351 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 14 PDB

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

Also linked: age related macular degeneration 14

For Immunodeficiency due to a classical component pathway complement deficiency (Orphanet):

Inheritance: Autosomal recessive

Similar variants

C2 p.Pro751Ser Uncertain significance ★ ⚠ same residue
C2 p.Pro751Thr Uncertain significance ★ ⚠ same residue
C2 c.1902+5G>A Uncertain significance ★★ 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
C2 p.Lys572Asn 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-pro751 (accessed [today's date]).

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