Is ROR2 p.Tyr678= (c.2034C>T) pathogenic?

ROR2 p.Tyr678= (c.2034C>T) is classified Conflicting classifications of pathogenicity in ROR2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-02-01). Ultra-rare (popmax 0.0165%, mid); Associated with brachydactyly type B1.

What condition is associated with ROR2 p.Tyr678= (c.2034C>T)?

ROR2 p.Tyr678= (c.2034C>T) is associated with brachydactyly type B1, autosomal recessive Robinow syndrome (ClinVar).

How common is ROR2 p.Tyr678= (c.2034C>T) in the general population?

ROR2 p.Tyr678= (c.2034C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

ROR2 p.Tyr678=

c.2034C>T · rs199681534 · VCV913199

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

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 -4.6	GERP -2.2
Overall
CADD	1.049	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00308%

Overall 0.00229% 37/1,614,196 alleles · ultra-rare exomes 27/1,461,838 · genomes 10/152,358 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
African / African-American	0.00933%	10,723
Remaining individualsnot grpmax-eligible	0.008%	12,502
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
East Asian	0.00223%	44,876
European (non-Finnish)	0.00178%	56,191
South Asian	0.0011%	91,084

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.Tyr678=
Coding: c.2034C>T
MANE Select: NM_004560
dbSNP: rs199681534
Type: single nucleotide variant
Location: chr9:91724460 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI 0.35 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 69.09 · 6 PDB
Residue 678: 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.Tyr678Ter Uncertain significance ★ same residue
ROR2 p.Tyr678Cys 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

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-tyr678 (accessed [today's date]).

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