Is ROR2 p.Arg568His (c.1703G>A) pathogenic?

ROR2 p.Arg568His (c.1703G>A) is classified Conflicting classifications of pathogenicity in ROR2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-08-02). AlphaMissense: likely benign (0.0975); Ultra-rare (popmax 0.0536%, eas); Associated with brachydactyly type B1.

What condition is associated with ROR2 p.Arg568His (c.1703G>A)?

ROR2 p.Arg568His (c.1703G>A) is associated with brachydactyly type B1, autosomal recessive Robinow syndrome (ClinVar).

How common is ROR2 p.Arg568His (c.1703G>A) in the general population?

ROR2 p.Arg568His (c.1703G>A) is ultra-rare (popmax 0.0536%, eas) (gnomAD).

What do computational predictors say about ROR2 p.Arg568His (c.1703G>A)?

AlphaMissense predicts likely benign (score 0.0975) — an in-silico prediction, not a clinical call.

ROR2 p.Arg568His

c.1703G>A · rs755191901 · VCV1597784

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0975 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0536%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

brachydactyly type B1

Computational evidence

Protein change
AlphaMissense	0.0975	likely benign
REVEL	0.53	indeterminate
SaProt	LLR -4.81	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 4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 226 kb · p 0.007 · regional, not allelic
Overall
CADD	23.7	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 0.0536% East Asian · 24/44,798 alleles

Filtering AF 0.0369% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0314%

Overall 0.00478% 77/1,610,278 alleles · ultra-rare exomes 74/1,458,084 · genomes 3/152,194 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0536%	1,867
South Asian	0.0275%	3,639
Admixed American	0.00667%	14,984
Remaining individualsnot grpmax-eligible	0.00642%	15,582
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,510
Finnishnot grpmax-eligible	0.00314%	31,881
European (non-Finnish)	0.00136%	73,572
African / African-American	0.00134%	74,842

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.Arg568His
Coding: c.1703G>A
MANE Select: NM_004560
dbSNP: rs755191901
Type: single nucleotide variant
Location: chr9:91724791 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI 0.35 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 69.09 · 6 PDB
Residue 568: the protein kinase domain

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.Arg568Cys Uncertain significance ★ ⚠ 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-arg568his (accessed [today's date]).

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