Is RAX2 p.Pro112fs (c.335del) pathogenic?

RAX2 p.Pro112fs (c.335del) is classified Uncertain significance in RAX2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-17). Very rare (popmax 0.0012%, sas).

How common is RAX2 p.Pro112fs (c.335del) in the general population?

RAX2 p.Pro112fs (c.335del) is very rare (popmax 0.0012%, sas) (gnomAD).

RAX2 p.Pro112fs

c.335del · VCV3665103

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0012%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (3 of 3) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -11	GERP -3.3
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0012% South Asian · 1/83,598 alleles

Overall 0.000262% 4/1,526,912 alleles · very rare exomes 3/1,374,812 · genomes 1/152,100 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00227%	44,048
Remaining individualsnot grpmax-eligible	0.00168%	59,452
South Asiangrpmax	0.0012%	83,598
European (non-Finnish)	8.75e-05%	1,142,589

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro112fs
Coding: c.335del
MANE Select: NM_001319074
Type: Deletion
Location: chr19:3770841 (GRCh38)
Gene constraint: LOEUF 1.525 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 71.72

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

Similar variants

RAX2 p.Pro112Leu Uncertain significance ★★ ⚠ same residue
RAX2 p.Pro112Arg Uncertain significance ★ ⚠ same residue
RAX2 p.Pro112Ser Uncertain significance ★ ⚠ same residue
RAX2 p.Pro112= Likely benign ★ same residue
RAX2 p.Pro112Thr Uncertain significance ⚠ same residue
RAX2 p.Ala156fs Pathogenic/Likely pathogenic ★★ same type
RAX2 c.182_216+254del Pathogenic ★ same type
RAX2 c.216+15del Benign ★ 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-pro112fs (accessed [today's date]).

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