Is RAX p.Pro288Gln (c.863C>A) pathogenic?

RAX p.Pro288Gln (c.863C>A) is classified Uncertain significance in RAX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-14). AlphaMissense: likely benign (0.1317); Ultra-rare (popmax 0.0966%, nfe); Associated with isolated microphthalmia 3.

What condition is associated with RAX p.Pro288Gln (c.863C>A)?

RAX p.Pro288Gln (c.863C>A) is associated with isolated microphthalmia 3 (ClinVar).

How common is RAX p.Pro288Gln (c.863C>A) in the general population?

RAX p.Pro288Gln (c.863C>A) is ultra-rare (popmax 0.0966%, nfe) (gnomAD).

What do computational predictors say about RAX p.Pro288Gln (c.863C>A)?

AlphaMissense predicts likely benign (score 0.1317) — an in-silico prediction, not a clinical call.

RAX p.Pro288Gln

c.863C>A · rs538022273 · VCV891347

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1317 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0966%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

isolated microphthalmia 3

Computational evidence

Protein change
AlphaMissense	0.1317	likely benign
REVEL	0.373	indeterminate
SaProt	LLR -12.86	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.8	GERP 0.72, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 4,199 bp · p 0.25 · regional, not allelic
Overall
CADD	21.5	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 0.0966% European (non-Finnish) · 1,110/1,148,662 alleles

Filtering AF 0.0919% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.09%

Overall 0.0739% 1,148/1,553,686 alleles · ultra-rare exomes 1,076/1,401,524 · genomes 72/152,162 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0966%	1,035
Remaining individualsnot grpmax-eligible	0.0348%	2,875
African / African-American	0.0177%	5,658
Finnishnot grpmax-eligible	0.00724%	13,805

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: RAX
Protein: p.Pro288Gln
Coding: c.863C>A
MANE Select: NM_013435
dbSNP: rs538022273
Type: single nucleotide variant
Location: chr18:59269182 (GRCh38)
Gene constraint: LOEUF 1.197 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 65.10
Residue 288: the 'disordered' region

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

Disease context

isolated microphthalmia 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RAX p.Pro288Ser Uncertain significance ★ ⚠ same residue
RAX c.*1300A>G Uncertain significance ★★ same condition
RAX c.*850C>T Uncertain significance ★★ same condition
RAX p.Ala267Val Uncertain significance ★★ ⚠ same condition
RAX p.Ala72Gly Uncertain significance ★★ ⚠ same condition
RAX p.Arg110Gly Uncertain significance ★★ ⚠ same condition
RAX p.Arg166Pro Uncertain significance ★★ ⚠ same condition
RAX p.Glu96Gln 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/rax-p-pro288gln (accessed [today's date]).

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