Is C2 p.Pro73Leu (c.218C>T) pathogenic?

C2 p.Pro73Leu (c.218C>T) is classified Conflicting classifications of pathogenicity in C2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-09-04). AlphaMissense: likely benign (0.0777); Low-frequency (popmax 1.2%, eas); Associated with complement component 2 deficiency.

What condition is associated with C2 p.Pro73Leu (c.218C>T)?

C2 p.Pro73Leu (c.218C>T) is associated with complement component 2 deficiency, age related macular degeneration 14 (ClinVar).

How common is C2 p.Pro73Leu (c.218C>T) in the general population?

C2 p.Pro73Leu (c.218C>T) is low-frequency (popmax 1.2%, eas) (gnomAD).

What do computational predictors say about C2 p.Pro73Leu (c.218C>T)?

AlphaMissense predicts likely benign (score 0.0777) — an in-silico prediction, not a clinical call.

C2 p.Pro73Leu

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.218C>T · rs137902889 · VCV356243

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0777 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.2%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

complement component 2 deficiency

Computational evidence

Protein change
AlphaMissense	0.0777	likely benign
REVEL	0.029	moderately benign-leaning
SaProt	LLR -6.24	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.3	GERP -3.4
Regional constraint	o/e 0.84	unconstrained · MANE · 18 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	4.476	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 1.2% East Asian · 540/44,880 alleles

Filtering AF 1.12% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.09%

Overall 0.035% 564/1,613,192 alleles · low-frequency

Ancestry group	Frequency	1 in
East Asiangrpmax	1.2%	83
Remaining individualsnot grpmax-eligible	0.0272%	3,676
South Asian	0.00439%	22,765
Admixed American	0.00333%	30,007
European (non-Finnish)	8.47e-05%	1,179,962

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.Pro73Leu
Coding: c.218C>T
MANE Select: NM_000063
dbSNP: rs137902889
Type: single nucleotide variant
Location: chr6:31928126 (GRCh38)
Gene constraint: LOEUF 0.909 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.61 · 14 PDB
Residue 73: a disulfide bond; the sushi 1 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

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.Pro73Ser 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
C2 p.Phe273= 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-pro73leu (accessed [today's date]).

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