Is C9 p.Pro47Leu (c.140C>T) pathogenic?

C9 p.Pro47Leu (c.140C>T) is classified Uncertain significance in C9 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-16). AlphaMissense: likely benign (0.115); Very rare (popmax 8.5e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with C9 p.Pro47Leu (c.140C>T)?

C9 p.Pro47Leu (c.140C>T) is associated with Inborn genetic diseases (ClinVar).

How common is C9 p.Pro47Leu (c.140C>T) in the general population?

C9 p.Pro47Leu (c.140C>T) is very rare (popmax 8.5e-05%, nfe) (gnomAD).

What do computational predictors say about C9 p.Pro47Leu (c.140C>T)?

AlphaMissense predicts likely benign (score 0.115) — an in-silico prediction, not a clinical call.

C9 p.Pro47Leu

c.140C>T · rs763505034 · VCV2250795

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.115 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.5e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.115	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	LLR -8.02	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 1.1, phastCons 0.36
Regional constraint	o/e 1.11	unconstrained · MANE · 79 kb · p 0.0043 · regional, not allelic
Overall
CADD	20.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.5e-05% European (non-Finnish) · 1/1,176,718 alleles

Overall 6.86e-05% 1/1,458,244 alleles · very rare

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.Pro47Leu
Coding: c.140C>T
MANE Select: NM_001737
dbSNP: rs763505034
Type: single nucleotide variant
Location: chr5:39342134 (GRCh38)
Gene constraint: LOEUF 1.223 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.32 · 9 PDB
Residue 47: a disulfide bond; an α-helix; the tsp type-1 domain

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.Ala497Val Uncertain significance ★★ ⚠ same condition
C9 p.Arg139His Uncertain significance ★★ ⚠ same condition
C9 p.Arg154Gln Uncertain significance ★★ ⚠ same condition
C9 p.Arg154Pro 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-pro47leu (accessed [today's date]).

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