Is RAX2 p.Arg78His (c.233G>A) pathogenic?

RAX2 p.Arg78His (c.233G>A) is classified Conflicting classifications of pathogenicity in RAX2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-03). AlphaMissense: likely pathogenic (0.9652); Ultra-rare (popmax 0.0171%, mid); Associated with RAX2-related disorder.

What condition is associated with RAX2 p.Arg78His (c.233G>A)?

RAX2 p.Arg78His (c.233G>A) is associated with RAX2-related disorder (ClinVar).

How common is RAX2 p.Arg78His (c.233G>A) in the general population?

RAX2 p.Arg78His (c.233G>A) is ultra-rare (popmax 0.0171%, mid) (gnomAD).

What do computational predictors say about RAX2 p.Arg78His (c.233G>A)?

AlphaMissense predicts likely pathogenic (score 0.9652) — an in-silico prediction, not a clinical call.

RAX2 p.Arg78His

c.233G>A · rs398124430 · VCV96231

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9652 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0171%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RAX2-related disorder

Computational evidence

Protein change
AlphaMissense	0.9652	likely pathogenic
REVEL	0.911	moderately pathogenic-leaning
SaProt	LLR -13.81	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 1.5	GERP -0.59, phastCons 0.99
Regional constraint	o/e 1.01	unconstrained · MANE · 1,118 bp · p 0.83 · regional, not allelic
Overall
CADD	25.2	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 0.0171% Middle Eastern · 1/5,860 alleles

Filtering AF 0.00735% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00528%

Overall 0.00134% 21/1,561,718 alleles · ultra-rare exomes 19/1,409,556 · genomes 2/152,162 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0171%	5,860
Admixed American	0.0148%	6,752
East Asian	0.00231%	43,344
African / African-American	0.00135%	74,264
South Asian	0.00115%	86,724
European (non-Finnish)	0.000775%	129,012

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.Arg78His
Coding: c.233G>A
MANE Select: NM_001319074
dbSNP: rs398124430
Type: single nucleotide variant
Location: chr19:3770943 (GRCh38)
Gene constraint: LOEUF 1.525 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 71.72
Residue 78: a DNA-binding region

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

Disease context

RAX2-related disorder

Similar variants

RAX2 p.Arg78= Likely benign ★★ same residue
RAX2 p.Arg78Cys Uncertain significance ★ ⚠ same residue
RAX2 p.Pro52Arg Likely pathogenic ★★ same condition
RAX2 c.216+1G>A Likely pathogenic ★ same condition
RAX2 c.-11A>G Likely pathogenic ★ same condition
RAX2 p.Arg79Gln Conflicting classifications of pathogenicity ★ ⚠ same condition
RAX2 p.Pro112Thr Uncertain significance ⚠ same condition
RAX2 c.-33T>C Benign 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/rax2-p-arg78his (accessed [today's date]).

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