Is ROR2 p.Arg522= (c.1566G>T) pathogenic?

ROR2 p.Arg522= (c.1566G>T) is classified Uncertain significance in ROR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). Ultra-rare (popmax 0.0357%, eas); Associated with brachydactyly type B1.

What condition is associated with ROR2 p.Arg522= (c.1566G>T)?

ROR2 p.Arg522= (c.1566G>T) is associated with brachydactyly type B1, autosomal recessive Robinow syndrome (ClinVar).

How common is ROR2 p.Arg522= (c.1566G>T) in the general population?

ROR2 p.Arg522= (c.1566G>T) is ultra-rare (popmax 0.0357%, eas) (gnomAD).

ROR2 p.Arg522=

c.1566G>T · rs755724416 · VCV914369

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0357%, eas)

Conditions

brachydactyly type B1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.18	GERP -2.5, phastCons 0.4
Overall
CADD	2.392	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0357% East Asian · 16/44,822 alleles

Filtering AF 0.0223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0182%

Overall 0.00105% 17/1,612,584 alleles · ultra-rare exomes 17/1,460,264 · genomes 0/152,320 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0357%	2,801
European (non-Finnish)	8.48e-05%	1,179,098

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: ROR2
Protein: p.Arg522=
Coding: c.1566G>T
MANE Select: NM_004560
dbSNP: rs755724416
Type: single nucleotide variant
Location: chr9:91724928 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI 0.35 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 69.09 · 6 PDB
Residue 522: the protein kinase domain; an α-helix

Full ROR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

brachydactyly type B1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive Robinow syndrome

Similar variants

ROR2 p.Arg522Trp Uncertain significance ★★ ⚠ same residue
ROR2 p.Arg522fs Likely pathogenic ★ same residue
ROR2 p.Arg522Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
ROR2 c.175+1G>A Likely pathogenic ★★ same condition
ROR2 p.Arg119Ter Pathogenic ★★ same condition
ROR2 p.Arg397Ter Pathogenic ★★ same condition
ROR2 p.Arg442Ter Pathogenic ★★ same condition
ROR2 p.Arg528Ter Pathogenic/Likely pathogenic ★★ 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/ror2-p-arg522 (accessed [today's date]).

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