Is RAX2 p.Arg179Ser (c.537G>C) pathogenic?

RAX2 p.Arg179Ser (c.537G>C) is classified Uncertain significance in RAX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-01). AlphaMissense: likely benign (0.2286); Very rare (popmax 0.00245%, eas); Associated with cone-rod dystrophy 11.

What condition is associated with RAX2 p.Arg179Ser (c.537G>C)?

RAX2 p.Arg179Ser (c.537G>C) is associated with cone-rod dystrophy 11, age related macular degeneration 6, retinitis pigmentosa 95 (ClinVar).

How common is RAX2 p.Arg179Ser (c.537G>C) in the general population?

RAX2 p.Arg179Ser (c.537G>C) is very rare (popmax 0.00245%, eas) (gnomAD).

How is Cone rod dystrophy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about RAX2 p.Arg179Ser (c.537G>C)?

AlphaMissense predicts likely benign (score 0.2286) — an in-silico prediction, not a clinical call.

RAX2 p.Arg179Ser

c.537G>C · VCV3892258

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2286 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00245%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

cone-rod dystrophy 11

Computational evidence

Protein change
AlphaMissense	0.2286	likely benign
REVEL	0.311	indeterminate
SaProt	LLR -5.92	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -0.69, phastCons 0.98
Regional constraint	o/e 1.01	unconstrained · MANE · 1,118 bp · p 0.83 · regional, not allelic
Overall
CADD	20.1	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 0.00245% East Asian · 1/40,842 alleles

Filtering AF 8.2e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.5e-05%

Overall 0.000326% 5/1,534,094 alleles · very rare exomes 5/1,381,728 · genomes 0/152,366 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00245%	40,842
European (non-Finnish)	0.000349%	286,563

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.Arg179Ser
Coding: c.537G>C
MANE Select: NM_001319074
Type: single nucleotide variant
Location: chr19:3770639 (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

Disease context

cone-rod dystrophy 11 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: age related macular degeneration 6 retinitis pigmentosa 95

For Cone rod dystrophy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

RAX2 p.Arg179Gly Uncertain significance ★★ ⚠ same residue
RAX2 c.*368C>T Uncertain significance ★★ same condition
RAX2 p.Ala45Val Uncertain significance ★★ ⚠ same condition
RAX2 p.Arg28Gln Uncertain significance ★★ ⚠ same condition
RAX2 p.Arg31His Uncertain significance ★★ ⚠ same condition
RAX2 p.Arg57Cys Uncertain significance ★★ ⚠ same condition
RAX2 p.Arg87Gln Uncertain significance ★★ ⚠ same condition
RAX2 p.His149Arg Uncertain significance ★★ ⚠ 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-arg179ser (accessed [today's date]).

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