Is ROR2 p.Glu563Lys (c.1687G>A) pathogenic?

ROR2 p.Glu563Lys (c.1687G>A) is classified Uncertain significance in ROR2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-09-02). AlphaMissense: likely pathogenic (0.8105); Ultra-rare (popmax 0.0156%, eas); Associated with brachydactyly type B1.

What condition is associated with ROR2 p.Glu563Lys (c.1687G>A)?

ROR2 p.Glu563Lys (c.1687G>A) is associated with brachydactyly type B1, autosomal recessive Robinow syndrome (ClinVar).

How common is ROR2 p.Glu563Lys (c.1687G>A) in the general population?

ROR2 p.Glu563Lys (c.1687G>A) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

What do computational predictors say about ROR2 p.Glu563Lys (c.1687G>A)?

AlphaMissense predicts likely pathogenic (score 0.8105) — an in-silico prediction, not a clinical call.

ROR2 p.Glu563Lys

c.1687G>A · rs186571882 · VCV1336627

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.8105 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

brachydactyly type B1

Computational evidence

Protein change
AlphaMissense	0.8105	likely pathogenic
REVEL	0.849	moderately pathogenic-leaning
SaProt	LLR -11.66	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	29.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0156% East Asian · 7/44,758 alleles

Filtering AF 0.00728% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00516%

Overall 0.00479% 77/1,608,756 alleles · ultra-rare exomes 75/1,456,418 · genomes 2/152,338 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,394
European (non-Finnish)	0.00536%	18,666
Admixed American	0.00334%	29,958
Remaining individualsnot grpmax-eligible	0.00321%	31,137
African / African-American	0.00267%	37,481
South Asian	0.0011%	90,778

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.Glu563Lys
Coding: c.1687G>A
MANE Select: NM_004560
dbSNP: rs186571882
Type: single nucleotide variant
Location: chr9:91724807 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI 0.35 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 69.09 · 6 PDB
Residue 563: 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.Glu563Gly 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-glu563lys (accessed [today's date]).

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