Is C9 p.Arg154Pro (c.461G>C) pathogenic?

C9 p.Arg154Pro (c.461G>C) is classified Uncertain significance in C9 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-17). AlphaMissense: likely pathogenic (0.9816); Very rare (popmax 0.000254%, nfe); Associated with Inborn genetic diseases.

What condition is associated with C9 p.Arg154Pro (c.461G>C)?

C9 p.Arg154Pro (c.461G>C) is associated with Inborn genetic diseases (ClinVar).

How common is C9 p.Arg154Pro (c.461G>C) in the general population?

C9 p.Arg154Pro (c.461G>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about C9 p.Arg154Pro (c.461G>C)?

AlphaMissense predicts likely pathogenic (score 0.9816) — an in-silico prediction, not a clinical call.

C9 p.Arg154Pro

c.461G>C · rs368001255 · VCV1982623

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9816 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9816	likely pathogenic · top 2% in C9
REVEL	0.274	benign-leaning
SaProt	LLR -1.93	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.2, phastCons 0.79
Regional constraint	o/e 1.11	unconstrained · MANE · 79 kb · p 0.0043 · regional, not allelic
Overall
CADD	24.6	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 0.000254% European (non-Finnish) · 3/1,180,022 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.00105% 17/1,614,050 alleles · very rare exomes 16/1,461,878 · genomes 1/152,172 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0405%	2,467
Remaining individualsnot grpmax-eligible	0.0032%	31,245
European (non-Finnish)grpmax	0.000254%	393,340

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg154Pro
Coding: c.461G>C
MANE Select: NM_001737
dbSNP: rs368001255
Type: single nucleotide variant
Location: chr5:39341161 (GRCh38)
Gene constraint: LOEUF 1.223 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.32 · 9 PDB
Residue 154: the macpf domain; a turn

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

C9 p.Arg154Gln Uncertain significance ★★ ⚠ same residue
C9 p.Arg154Ter Pathogenic/Likely pathogenic ★★ same residue
C9 p.Ala497Val Uncertain significance ★★ ⚠ same condition
C9 p.Arg139His Uncertain significance ★★ ⚠ same condition
C9 p.Arg369Gln Uncertain significance ★★ ⚠ same condition
C9 p.Arg369Trp Uncertain significance ★★ ⚠ same condition
C9 p.Arg63His Uncertain significance ★★ ⚠ same condition
C9 p.Asn182Lys 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/c9-p-arg154pro (accessed [today's date]).

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