Is C9 p.Met484Lys (c.1451T>A) pathogenic?

C9 p.Met484Lys (c.1451T>A) is classified Conflicting classifications of pathogenicity in C9 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-03). AlphaMissense: ambiguous (0.4253); Rare (popmax 0.38%, afr); Associated with complement component 9 deficiency.

What condition is associated with C9 p.Met484Lys (c.1451T>A)?

C9 p.Met484Lys (c.1451T>A) is associated with complement component 9 deficiency, age related macular degeneration 15 (ClinVar).

How common is C9 p.Met484Lys (c.1451T>A) in the general population?

C9 p.Met484Lys (c.1451T>A) is rare (popmax 0.38%, afr) (gnomAD).

What do computational predictors say about C9 p.Met484Lys (c.1451T>A)?

AlphaMissense predicts ambiguous (score 0.4253) — an in-silico prediction, not a clinical call.

C9 p.Met484Lys

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.1451T>A · rs145969667 · VCV1546178

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4253 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.38%, afr)

Conditions

complement component 9 deficiency

Computational evidence

Protein change
AlphaMissense	0.4253	ambiguous
REVEL	0.437	indeterminate
SaProt	LLR -11.66	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 79 kb · p 0.0043 · regional, not allelic
Overall
CADD	23.4	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 0.38% African / African-American · 284/74,802 alleles

Filtering AF 0.343% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.329%

Overall 0.0188% 303/1,609,230 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.38%	263
Admixed American	0.0184%	5,437
Remaining individualsnot grpmax-eligible	0.00802%	12,462
European (non-Finnish)	0.000255%	392,055

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.Met484Lys
Coding: c.1451T>A
MANE Select: NM_001737
dbSNP: rs145969667
Type: single nucleotide variant
Location: chr5:39288917 (GRCh38)
Gene constraint: LOEUF 1.223 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.32 · 9 PDB
Residue 484: the macpf domain; a β-strand

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

Also linked: age related macular degeneration 15

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-met484lys (accessed [today's date]).

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