Is C5 p.Ser1067Arg (c.3199A>C) pathogenic?

C5 p.Ser1067Arg (c.3199A>C) is classified Uncertain significance in C5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-06-23). AlphaMissense: likely pathogenic (0.8079); Ultra-rare (popmax 0.0197%, nfe); Associated with complement component 5 deficiency.

What condition is associated with C5 p.Ser1067Arg (c.3199A>C)?

C5 p.Ser1067Arg (c.3199A>C) is associated with complement component 5 deficiency (ClinVar).

How common is C5 p.Ser1067Arg (c.3199A>C) in the general population?

C5 p.Ser1067Arg (c.3199A>C) is ultra-rare (popmax 0.0197%, nfe) (gnomAD).

What do computational predictors say about C5 p.Ser1067Arg (c.3199A>C)?

AlphaMissense predicts likely pathogenic (score 0.8079) — an in-silico prediction, not a clinical call.

C5 p.Ser1067Arg

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.3199A>C · rs377417930 · VCV1420926

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8079 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0197%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

complement component 5 deficiency

Computational evidence

Protein change
AlphaMissense	0.8079	likely pathogenic · top 9% in C5
REVEL	0.235	benign-leaning
SaProt	LLR -12.67	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 2, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 98 kb · p 1.2e-09 · regional, not allelic
Overall
CADD	25.0	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 0.0197% European (non-Finnish) · 233/1,179,812 alleles

Filtering AF 0.0177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0168%

Overall 0.0162% 262/1,613,820 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0197%	5,064
Remaining individualsnot grpmax-eligible	0.0192%	5,205
Admixed American	0.0167%	6,000
African / African-American	0.00934%	10,703

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.Ser1067Arg
Coding: c.3199A>C
MANE Select: NM_001735
dbSNP: rs377417930
Type: single nucleotide variant
Location: chr9:120989077 (GRCh38)
Gene constraint: LOEUF 0.779 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.67 · 49 PDB
Residue 1067: a β-strand; a disulfide bond; a UniProt-annotated variant site (in c5d)

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 p.Ser1067= Likely benign ★ same residue
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

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-ser1067arg (accessed [today's date]).

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