Is RAX2 p.Pro9Leu (c.26C>T) pathogenic?

RAX2 p.Pro9Leu (c.26C>T) is classified Uncertain significance in RAX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-01). AlphaMissense: likely benign (0.0801); Very rare (popmax 0.00221%, sas).

How common is RAX2 p.Pro9Leu (c.26C>T) in the general population?

RAX2 p.Pro9Leu (c.26C>T) is very rare (popmax 0.00221%, sas) (gnomAD).

What do computational predictors say about RAX2 p.Pro9Leu (c.26C>T)?

AlphaMissense predicts likely benign (score 0.0801) — an in-silico prediction, not a clinical call.

RAX2 p.Pro9Leu

c.26C>T · VCV4151154

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0801 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00221%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0801	likely benign
REVEL	0.108	moderately benign-leaning
SaProt	LLR -7.36	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.016	GERP -4
Regional constraint	o/e 1.01	unconstrained · MANE · 1,118 bp · p 0.83 · regional, not allelic
Overall
CADD	12.83	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 0.00221% South Asian · 2/90,688 alleles

Filtering AF 0.000366% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000435% 7/1,607,754 alleles · very rare exomes 6/1,455,628 · genomes 1/152,126 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00221%	45,344
Finnishnot grpmax-eligible	0.00167%	59,740
Remaining individualsnot grpmax-eligible	0.0016%	62,310
African / African-American	0.00134%	74,874
European (non-Finnish)	0.00017%	589,504

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: RAX2
Protein: p.Pro9Leu
Coding: c.26C>T
MANE Select: NM_001319074
Type: single nucleotide variant
Location: chr19:3771717 (GRCh38)
Gene constraint: LOEUF 1.525 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 71.72
Residue 9: the 'disordered' region

Full RAX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RAX2 p.Pro9= Likely benign ★ same residue
RAX2 p.Pro52Arg Likely pathogenic ★★ same type
RAX2 c.217-12C>A Uncertain significance ★★ same type
RAX2 c.*368C>T Uncertain significance ★★ same type
RAX2 p.Ala105Val Uncertain significance ★★ ⚠ same type
RAX2 p.Ala109Thr Uncertain significance ★★ ⚠ same type
RAX2 p.Ala160Val Uncertain significance ★★ ⚠ same type
RAX2 p.Ala164Val Uncertain significance ★★ ⚠ same type

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/rax2-p-pro9leu (accessed [today's date]).

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