Is ROR2 p.Phe226= (c.678C>T) pathogenic?

ROR2 p.Phe226= (c.678C>T) is classified Conflicting classifications of pathogenicity in ROR2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-06). Ultra-rare (popmax 0.099%, mid); Associated with brachydactyly type B1.

What condition is associated with ROR2 p.Phe226= (c.678C>T)?

ROR2 p.Phe226= (c.678C>T) is associated with brachydactyly type B1, autosomal recessive Robinow syndrome (ClinVar).

How common is ROR2 p.Phe226= (c.678C>T) in the general population?

ROR2 p.Phe226= (c.678C>T) is ultra-rare (popmax 0.099%, mid) (gnomAD).

ROR2 p.Phe226=

c.678C>T · rs202159869 · VCV290687

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.099%, 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 -0.65	GERP -1.6
Overall
CADD	11.17	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.099% Middle Eastern · 6/6,062 alleles

Filtering AF 0.043% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0294%

Overall 0.00199% 32/1,611,940 alleles · ultra-rare exomes 23/1,459,594 · genomes 9/152,346 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.099%	1,010
Admixed American	0.0133%	7,501
Remaining individualsnot grpmax-eligible	0.00961%	10,411
African / African-American	0.00666%	15,011
East Asian	0.00223%	44,856
Finnishnot grpmax-eligible	0.00161%	62,276
European (non-Finnish)	0.000424%	235,934

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.Phe226=
Coding: c.678C>T
MANE Select: NM_004560
dbSNP: rs202159869
Type: single nucleotide variant
Location: chr9:91733381 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI 0.35 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 69.09 · 6 PDB
Residue 226: an α-helix; the fz 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 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
ROR2 c.*135G>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-phe226 (accessed [today's date]).

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