Is C5 p.Met1Arg (c.2T>G) pathogenic?

C5 p.Met1Arg (c.2T>G) is classified Uncertain significance in C5 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-09). Very rare (popmax 0.00132%, nfe); Associated with complement component 5 deficiency.

What condition is associated with C5 p.Met1Arg (c.2T>G)?

C5 p.Met1Arg (c.2T>G) is associated with complement component 5 deficiency (ClinVar).

How common is C5 p.Met1Arg (c.2T>G) in the general population?

C5 p.Met1Arg (c.2T>G) is very rare (popmax 0.00132%, nfe) (gnomAD).

C5 p.Met1Arg

Q: How is Immunodeficiency due to a late component of complement deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.2T>G · VCV3778970

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00132%, nfe)

Conditions

complement component 5 deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.071	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.56	GERP -2.6
Overall
CADD	5.526	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 0.00132% European (non-Finnish) · 3/226,960 alleles

Filtering AF 0.000352% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.8e-05%

Overall 0.000987% 3/303,894 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: C5
Protein: p.Met1Arg
Coding: c.2T>G
MANE Select: NM_001735 · reported on NM_001317163
Type: single nucleotide variant
Location: chr9:121074835 (GRCh38)
Gene constraint: LOEUF 0.779 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.67 · 49 PDB

Full C5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

complement component 5 deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Immunodeficiency due to a late component of complement deficiency (Orphanet):

Inheritance: Autosomal recessive

Similar variants

C5 c.2257+1G>A Likely pathogenic ★★ same condition
C5 c.4679-2A>G Likely pathogenic ★★ same condition
C5 p.Arg1476Ter Pathogenic/Likely pathogenic ★★ same condition
C5 p.Gln19Ter Pathogenic ★★ same condition
C5 p.Trp469Ter Pathogenic/Likely pathogenic ★★ same condition
C5 c.2059+3A>G Uncertain significance ★★ same condition
C5 c.4081-6A>G Uncertain significance ★★ same condition
C5 c.4504+4A>G 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/c5-p-met1arg (accessed [today's date]).

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