Is C9 p.Glu137Lys (c.409G>A) pathogenic?

C9 p.Glu137Lys (c.409G>A) is classified Conflicting classifications of pathogenicity in C9 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-10-17). AlphaMissense: likely benign (0.1298); Very rare (popmax 0.00439%, sas); Associated with complement component 9 deficiency.

What condition is associated with C9 p.Glu137Lys (c.409G>A)?

C9 p.Glu137Lys (c.409G>A) is associated with complement component 9 deficiency (ClinVar).

How common is C9 p.Glu137Lys (c.409G>A) in the general population?

C9 p.Glu137Lys (c.409G>A) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about C9 p.Glu137Lys (c.409G>A)?

AlphaMissense predicts likely benign (score 0.1298) — an in-silico prediction, not a clinical call.

C9 p.Glu137Lys

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.409G>A · rs753246845 · VCV1033863

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1298 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

complement component 9 deficiency

Computational evidence

Protein change
AlphaMissense	0.1298	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -5.95	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.65	donor gain · deltas
Pangolin	Δ0.31	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5.9	GERP 2.1, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 79 kb · p 0.0043 · regional, not allelic
Overall
CADD	24.9	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 0.00439% South Asian · 4/91,080 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000547% 8/1,461,876 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00439%	22,770
European (non-Finnish)	0.000339%	295,007

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: C9
Protein: p.Glu137Lys
Coding: c.409G>A
MANE Select: NM_001737
dbSNP: rs753246845
Type: single nucleotide variant
Location: chr5:39341213 (GRCh38)
Gene constraint: LOEUF 1.223 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.32 · 9 PDB

Full C9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

complement component 9 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

C9 p.Arg116Ter Pathogenic/Likely pathogenic ★★ same condition
C9 p.Arg154Ter Pathogenic/Likely pathogenic ★★ same condition
C9 p.Arg194Ter Pathogenic/Likely pathogenic ★★ same condition
C9 p.Cys54Ter Pathogenic/Likely pathogenic ★★ same condition
C9 p.Gly126Arg Uncertain significance ★★ ⚠ same condition
C9 p.Ala325Val Likely benign ★★ ⚠ same condition
C9 p.Met45Leu Likely benign ★★ same condition
C9 c.184-1G>A Likely pathogenic ★ 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/c9-p-glu137lys (accessed [today's date]).

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