Is C9 p.Ala325Val (c.974C>T) pathogenic?

C9 p.Ala325Val (c.974C>T) is classified Likely benign in C9 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-29). AlphaMissense: likely benign (0.1291); Rare (popmax 0.344%, afr); Associated with age related macular degeneration 15.

What condition is associated with C9 p.Ala325Val (c.974C>T)?

C9 p.Ala325Val (c.974C>T) is associated with age related macular degeneration 15, complement component 9 deficiency (ClinVar).

How common is C9 p.Ala325Val (c.974C>T) in the general population?

C9 p.Ala325Val (c.974C>T) is rare (popmax 0.344%, afr) (gnomAD).

What do computational predictors say about C9 p.Ala325Val (c.974C>T)?

AlphaMissense predicts likely benign (score 0.1291) — an in-silico prediction, not a clinical call.

C9 p.Ala325Val

c.974C>T · rs147068084 · VCV1299281

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1291 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.344%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

age related macular degeneration 15

Computational evidence

Protein change
AlphaMissense	0.1291	likely benign
REVEL	0.324	indeterminate
SaProt	LLR -8.56	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.28 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.1	GERP 0.39, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 79 kb · p 0.0043 · regional, not allelic
Overall
CADD	15.89	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 0.344% African / African-American · 258/75,004 alleles

Filtering AF 0.31% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.296%

Overall 0.0167% 269/1,613,734 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.344%	291
Remaining individualsnot grpmax-eligible	0.0112%	8,928
Admixed American	0.00667%	14,997

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.Ala325Val
Coding: c.974C>T
MANE Select: NM_001737
dbSNP: rs147068084
Type: single nucleotide variant
Location: chr5:39311274 (GRCh38)
Gene constraint: LOEUF 1.223 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.32 · 9 PDB
Residue 325: the macpf domain

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

Disease context

Also linked: complement component 9 deficiency

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.Met45Leu Likely benign ★★ same condition
C9 c.184-1G>A Likely pathogenic ★ same condition
C9 p.Cys125Ter 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-ala325val (accessed [today's date]).

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