Is GP9 p.Pro2Leu (c.5C>T) pathogenic?

GP9 p.Pro2Leu (c.5C>T) is classified Uncertain significance in GP9 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-24). AlphaMissense: likely benign (0.0881); Very rare (popmax 0.0044%, sas); Associated with Inborn genetic diseases.

What condition is associated with GP9 p.Pro2Leu (c.5C>T)?

GP9 p.Pro2Leu (c.5C>T) is associated with Inborn genetic diseases (ClinVar).

How common is GP9 p.Pro2Leu (c.5C>T) in the general population?

GP9 p.Pro2Leu (c.5C>T) is very rare (popmax 0.0044%, sas) (gnomAD).

What do computational predictors say about GP9 p.Pro2Leu (c.5C>T)?

AlphaMissense predicts likely benign (score 0.0881) — an in-silico prediction, not a clinical call.

GP9 p.Pro2Leu

c.5C>T · VCV3854814

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0881 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0044%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0881	likely benign
REVEL	0.137	moderately benign-leaning
SaProt	LLR -5.16	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.42	GERP -0.65
Regional constraint	o/e 0.94	unconstrained · MANE · 530 bp · p 0.38 · regional, not allelic
Overall
CADD	9.082	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 0.0044% South Asian · 4/90,852 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000893%

Overall 0.00031% 5/1,612,204 alleles · very rare exomes 5/1,459,864 · genomes 0/152,340 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0044%	22,713
Remaining individualsnot grpmax-eligible	0.0016%	62,402

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: GP9
Protein: p.Pro2Leu
Coding: c.5C>T
MANE Select: NM_000174
Type: single nucleotide variant
Location: chr3:129061744 (GRCh38)
Structure: AlphaFold pLDDT 84.43 · 2 PDB

Full GP9 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

GP9 p.Ala51Asp Uncertain significance ★★ ⚠ same condition
GP9 p.Arg52Cys Uncertain significance ★★ ⚠ same condition
GP9 p.Asp81Asn Uncertain significance ★★ ⚠ same condition
GP9 p.Gly129Ser Uncertain significance ★★ ⚠ same condition
GP9 p.Gly167Ser Uncertain significance ★★ ⚠ same condition
GP9 p.Gly42Arg Uncertain significance ★★ ⚠ same condition
GP9 p.Ala141Val Uncertain significance ★ ⚠ same condition
GP9 p.Ala158Asp 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/gp9-p-pro2leu (accessed [today's date]).

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