Is ROR2 p.Arg657His (c.1970G>A) pathogenic?

ROR2 p.Arg657His (c.1970G>A) is classified Conflicting classifications of pathogenicity in ROR2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-08). AlphaMissense: likely pathogenic (0.9163); Very rare (popmax 0.0011%, sas); Associated with Brachydactyly, type B1Robinow syndrome, autosomal recessive.

What condition is associated with ROR2 p.Arg657His (c.1970G>A)?

ROR2 p.Arg657His (c.1970G>A) is associated with Brachydactyly, type B1Robinow syndrome, autosomal recessive, brachydactyly type B1, autosomal recessive Robinow syndrome (ClinVar).

How common is ROR2 p.Arg657His (c.1970G>A) in the general population?

ROR2 p.Arg657His (c.1970G>A) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about ROR2 p.Arg657His (c.1970G>A)?

AlphaMissense predicts likely pathogenic (score 0.9163) — an in-silico prediction, not a clinical call.

ROR2 p.Arg657His

c.1970G>A · rs529829552 · VCV159813

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9163 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Brachydactyly, type B1Robinow syndrome, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.9163	likely pathogenic
REVEL	0.927	moderately pathogenic-leaning
SaProt	LLR -14.51	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 226 kb · p 0.007 · regional, not allelic
Overall
CADD	32.0	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 0.0011% South Asian · 1/91,078 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000867% 14/1,614,174 alleles · very rare exomes 12/1,461,852 · genomes 2/152,322 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	64,016
South Asiangrpmax	0.0011%	91,078
European (non-Finnish)	0.00102%	98,335

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg657His
Coding: c.1970G>A
MANE Select: NM_004560
dbSNP: rs529829552
Type: single nucleotide variant
Location: chr9:91724524 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI 0.35 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 69.09 · 6 PDB
Residue 657: 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 B1Robinow syndrome, autosomal recessive

Also linked: brachydactyly type B1 autosomal recessive Robinow syndrome

Similar variants

ROR2 p.Arg657Cys 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-arg657his (accessed [today's date]).

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