Is ROR2 p.Arg178Gln (c.533G>A) pathogenic?

ROR2 p.Arg178Gln (c.533G>A) is classified Uncertain significance in ROR2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-19). AlphaMissense: likely pathogenic (0.8724); Ultra-rare (popmax 0.0133%, amr); Associated with Inborn genetic diseases.

What condition is associated with ROR2 p.Arg178Gln (c.533G>A)?

ROR2 p.Arg178Gln (c.533G>A) is associated with Inborn genetic diseases, brachydactyly type B1, autosomal recessive Robinow syndrome (ClinVar).

How common is ROR2 p.Arg178Gln (c.533G>A) in the general population?

ROR2 p.Arg178Gln (c.533G>A) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about ROR2 p.Arg178Gln (c.533G>A)?

AlphaMissense predicts likely pathogenic (score 0.8724) — an in-silico prediction, not a clinical call.

ROR2 p.Arg178Gln

c.533G>A · rs746562213 · VCV1053432

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8724 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8724	likely pathogenic
REVEL	0.619	indeterminate
SaProt	LLR -8.22	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6	GERP 2.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 226 kb · p 0.007 · regional, not allelic
Overall
CADD	28.8	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 0.0133% Admixed American · 8/59,998 alleles

Filtering AF 0.00661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.00136% 22/1,614,026 alleles · ultra-rare exomes 20/1,461,884 · genomes 2/152,142 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,500
African / African-American	0.00133%	74,916
European (non-Finnish)	0.0011%	90,772

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.Arg178Gln
Coding: c.533G>A
MANE Select: NM_004560
dbSNP: rs746562213
Type: single nucleotide variant
Location: chr9:91737480 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI 0.35 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 69.09 · 6 PDB
Residue 178: the fz domain

Full ROR2 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: brachydactyly type B1 autosomal recessive Robinow syndrome

Similar variants

ROR2 p.Arg178Trp 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
ROR2 c.175+3G>T Uncertain significance ★★ same condition
ROR2 c.-102G>T 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/ror2-p-arg178gln (accessed [today's date]).

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