Is RAX p.Leu289Phe (c.867G>T) pathogenic?

RAX p.Leu289Phe (c.867G>T) is classified Uncertain significance in RAX (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-21). AlphaMissense: likely benign (0.1074); Ultra-rare (popmax 0.0243%, sas); Associated with Inborn genetic diseases.

What condition is associated with RAX p.Leu289Phe (c.867G>T)?

RAX p.Leu289Phe (c.867G>T) is associated with Inborn genetic diseases, isolated microphthalmia 3 (ClinVar).

How common is RAX p.Leu289Phe (c.867G>T) in the general population?

RAX p.Leu289Phe (c.867G>T) is ultra-rare (popmax 0.0243%, sas) (gnomAD).

What do computational predictors say about RAX p.Leu289Phe (c.867G>T)?

AlphaMissense predicts likely benign (score 0.1074) — an in-silico prediction, not a clinical call.

RAX p.Leu289Phe

c.867G>T · rs770271072 · VCV2055375

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1074 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0243%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1074	likely benign
REVEL	0.389	indeterminate
SaProt	LLR -7.47	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 0.63	GERP 1.9, phastCons 0.98
Regional constraint	o/e 1.05	unconstrained · MANE · 4,199 bp · p 0.25 · regional, not allelic
Overall
CADD	21.3	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 0.0243% South Asian · 21/86,280 alleles

Filtering AF 0.0163% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00687% 107/1,558,106 alleles · ultra-rare exomes 101/1,406,042 · genomes 6/152,064 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0243%	4,109
Remaining individualsnot grpmax-eligible	0.0182%	5,498
Admixed American	0.00938%	10,664
European (non-Finnish)	0.00591%	16,924
African / African-American	0.00272%	36,805

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.Leu289Phe
Coding: c.867G>T
MANE Select: NM_013435
dbSNP: rs770271072
Type: single nucleotide variant
Location: chr18:59269178 (GRCh38)
Gene constraint: LOEUF 1.197 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 65.10
Residue 289: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: isolated microphthalmia 3

Similar variants

RAX p.Leu289Met 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-leu289phe (accessed [today's date]).

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