Is RAX2 p.Ser4Arg (c.12C>G) pathogenic?

RAX2 p.Ser4Arg (c.12C>G) is classified Likely benign in RAX2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-13). AlphaMissense: ambiguous (0.4535); Rare (popmax 0.242%, eas).

How common is RAX2 p.Ser4Arg (c.12C>G) in the general population?

RAX2 p.Ser4Arg (c.12C>G) is rare (popmax 0.242%, eas) (gnomAD).

What do computational predictors say about RAX2 p.Ser4Arg (c.12C>G)?

AlphaMissense predicts ambiguous (score 0.4535) — an in-silico prediction, not a clinical call.

RAX2 p.Ser4Arg

c.12C>G · rs201416315 · VCV1579185

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4535 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.242%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4535	ambiguous
REVEL	0.173	moderately benign-leaning
SaProt	LLR -6.87	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -4.1, phastCons 0.93
Regional constraint	o/e 1.01	unconstrained · MANE · 1,118 bp · p 0.83 · regional, not allelic
Overall
CADD	18.06	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 0.242% East Asian · 108/44,708 alleles

Filtering AF 0.205% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.191%

Overall 0.00699% 112/1,602,178 alleles · rare exomes 96/1,449,914 · genomes 16/152,264 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.242%	414
Remaining individualsnot grpmax-eligible	0.00322%	31,088
European (non-Finnish)	0.00017%	588,755

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.Ser4Arg
Coding: c.12C>G
MANE Select: NM_001319074
dbSNP: rs201416315
Type: single nucleotide variant
Location: chr19:3771731 (GRCh38)
Gene constraint: LOEUF 1.525 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 71.72
Residue 4: the 'disordered' region

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

Similar variants

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
RAX2 p.Ala180Pro 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-ser4arg (accessed [today's date]).

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