Is RAX2 p.Ala45Val (c.134C>T) pathogenic?

RAX2 p.Ala45Val (c.134C>T) is classified Uncertain significance in RAX2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-07-27). AlphaMissense: likely pathogenic (0.6899); Very rare (popmax 0.00195%, nfe); Associated with cone-rod dystrophy 11.

What condition is associated with RAX2 p.Ala45Val (c.134C>T)?

RAX2 p.Ala45Val (c.134C>T) is associated with cone-rod dystrophy 11, age related macular degeneration 6, inherited retinal dystrophy (ClinVar).

How common is RAX2 p.Ala45Val (c.134C>T) in the general population?

RAX2 p.Ala45Val (c.134C>T) is very rare (popmax 0.00195%, nfe) (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.Ala45Val (c.134C>T)?

AlphaMissense predicts likely pathogenic (score 0.6899) — an in-silico prediction, not a clinical call.

RAX2 p.Ala45Val

c.134C>T · rs775581464 · VCV892559

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.6899 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00195%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

cone-rod dystrophy 11

Computational evidence

Protein change
AlphaMissense	0.6899	likely pathogenic
REVEL	0.606	indeterminate
SaProt	LLR -10.86	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.3	GERP -0.3, phastCons 0.89
Regional constraint	o/e 1.01	unconstrained · MANE · 1,118 bp · p 0.83 · regional, not allelic
Overall
CADD	23.5	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 0.00195% European (non-Finnish) · 23/1,179,612 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00149% 24/1,612,352 alleles · very rare exomes 23/1,460,186 · genomes 1/152,166 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00195%	51,288
African / African-American	0.00133%	74,916

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.Ala45Val
Coding: c.134C>T
MANE Select: NM_001319074
dbSNP: rs775581464
Type: single nucleotide variant
Location: chr19:3771609 (GRCh38)
Gene constraint: LOEUF 1.525 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 71.72
Residue 45: a DNA-binding region

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 inherited retinal dystrophy

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.Ala45Thr Uncertain significance ★ ⚠ same residue
RAX2 p.Ala45= Likely benign ★ same residue
RAX2 c.*368C>T Uncertain significance ★★ same condition
RAX2 p.Arg179Gly Uncertain significance ★★ ⚠ same condition
RAX2 p.Arg28Gln Uncertain significance ★★ ⚠ same condition
RAX2 p.Arg31His Uncertain significance ★★ ⚠ same condition
RAX2 p.Arg83Cys Uncertain significance ★★ ⚠ same condition
RAX2 p.Arg87Gln 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-ala45val (accessed [today's date]).

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