Is RAX2 p.Arg84His (c.251G>A) pathogenic?

RAX2 p.Arg84His (c.251G>A) is classified Uncertain significance in RAX2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-01-27). AlphaMissense: likely pathogenic (0.8347); Very rare (popmax 0.00462%, sas).

How common is RAX2 p.Arg84His (c.251G>A) in the general population?

RAX2 p.Arg84His (c.251G>A) is very rare (popmax 0.00462%, sas) (gnomAD).

What do computational predictors say about RAX2 p.Arg84His (c.251G>A)?

AlphaMissense predicts likely pathogenic (score 0.8347) — an in-silico prediction, not a clinical call.

RAX2 p.Arg84His

c.251G>A · rs573043030 · VCV1478358

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8347 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00462%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8347	likely pathogenic
REVEL	0.778	moderately pathogenic-leaning
SaProt	LLR -13.90	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.64	GERP -1.9, phastCons 0.77
Regional constraint	o/e 1.01	unconstrained · MANE · 1,118 bp · p 0.83 · regional, not allelic
Overall
CADD	22.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00462% South Asian · 4/86,522 alleles

Filtering AF 0.00158% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000987%

Overall 0.00173% 27/1,560,954 alleles · very rare exomes 24/1,408,682 · genomes 3/152,272 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00462%	21,631
Finnishnot grpmax-eligible	0.0022%	45,496
European (non-Finnish)	0.00181%	55,279
Remaining individualsnot grpmax-eligible	0.00164%	61,064

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.Arg84His
Coding: c.251G>A
MANE Select: NM_001319074
dbSNP: rs573043030
Type: single nucleotide variant
Location: chr19:3770925 (GRCh38)
Gene constraint: LOEUF 1.525 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 71.72
Residue 84: a DNA-binding region

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

Similar variants

RAX2 p.Arg84Cys Uncertain significance ★★ ⚠ same residue
RAX2 p.Arg84= 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

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-arg84his (accessed [today's date]).

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