Is RAX2 p.Pro52Leu (c.155C>T) pathogenic?

RAX2 p.Pro52Leu (c.155C>T) is classified Benign in RAX2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-02-01). AlphaMissense: likely pathogenic (0.981); Low-frequency (popmax 2.19%, nfe); Associated with age related macular degeneration 6.

What condition is associated with RAX2 p.Pro52Leu (c.155C>T)?

RAX2 p.Pro52Leu (c.155C>T) is associated with age related macular degeneration 6, cone-rod dystrophy 11, retinitis pigmentosa 95 (ClinVar).

How common is RAX2 p.Pro52Leu (c.155C>T) in the general population?

RAX2 p.Pro52Leu (c.155C>T) is low-frequency (popmax 2.19%, nfe) (gnomAD).

What do computational predictors say about RAX2 p.Pro52Leu (c.155C>T)?

AlphaMissense predicts likely pathogenic (score 0.981) — an in-silico prediction, not a clinical call.

RAX2 p.Pro52Leu

c.155C>T · rs76076446 · VCV96229

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.981 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.19%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

age related macular degeneration 6

Computational evidence

Protein change
AlphaMissense	0.981	likely pathogenic
REVEL	0.734	pathogenic-leaning
SaProt	LLR -11.43	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 5.2	GERP 2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 1,118 bp · p 0.83 · regional, not allelic
Overall
CADD	25.9	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 2.19% European (non-Finnish) · 25,776/1,179,308 alleles

Filtering AF 2.16% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.15%

Overall 1.86% 29,958/1,611,622 alleles · low-frequency exomes 27,782/1,459,338 · genomes 2,176/152,284 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	2.9%	34
European (non-Finnish)grpmax	2.19%	46
Remaining individualsnot grpmax-eligible	1.64%	61
Admixed American	0.953%	105
Middle Eastern	0.66%	152
Ashkenazi Jewishnot grpmax-eligible	0.461%	217
African / African-American	0.377%	265
South Asian	0.323%	309
Amishnot grpmax-eligible	0.219%	456

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.Pro52Leu
Coding: c.155C>T
MANE Select: NM_001319074
dbSNP: rs76076446
Type: single nucleotide variant
Location: chr19:3771588 (GRCh38)
Gene constraint: LOEUF 1.525 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 71.72
Residue 52: a DNA-binding region; a UniProt-annotated variant site (in rp95)

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

Disease context

Also linked: cone-rod dystrophy 11 retinitis pigmentosa 95

Similar variants

RAX2 p.Pro52Arg Likely pathogenic ★★ same residue
RAX2 p.Pro52= Likely benign ★ same residue
RAX2 c.*368C>T Uncertain significance ★★ same condition
RAX2 p.Ala45Val 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.Arg57Cys 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-pro52leu (accessed [today's date]).

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