Is ROR2 p.Arg280Leu (c.839G>T) pathogenic?

ROR2 p.Arg280Leu (c.839G>T) is classified Uncertain significance in ROR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-16). AlphaMissense: ambiguous (0.3608); Very rare (popmax 0.00133%, afr); Associated with autosomal recessive Robinow syndrome.

What condition is associated with ROR2 p.Arg280Leu (c.839G>T)?

ROR2 p.Arg280Leu (c.839G>T) is associated with autosomal recessive Robinow syndrome, brachydactyly type B1 (ClinVar).

How common is ROR2 p.Arg280Leu (c.839G>T) in the general population?

ROR2 p.Arg280Leu (c.839G>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ROR2 p.Arg280Leu (c.839G>T)?

AlphaMissense predicts ambiguous (score 0.3608) — an in-silico prediction, not a clinical call.

ROR2 p.Arg280Leu

c.839G>T · VCV3597768

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3608 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

autosomal recessive Robinow syndrome

Computational evidence

Protein change
AlphaMissense	0.3608	ambiguous
REVEL	0.133	moderately benign-leaning
SaProt	LLR -4.38	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP -0.39, phastCons 0.98
Regional constraint	o/e 0.93	unconstrained · MANE · 226 kb · p 0.007 · regional, not allelic
Overall
CADD	23.5	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 0.00133% African / African-American · 1/75,040 alleles

Overall 0.000124% 2/1,612,340 alleles · very rare exomes 2/1,460,018 · genomes 0/152,322 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00158%	63,178
African / African-Americangrpmax	0.00133%	75,040

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.Arg280Leu
Coding: c.839G>T
MANE Select: NM_004560
Type: single nucleotide variant
Location: chr9:91733220 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI 0.35 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 69.09 · 6 PDB
Residue 280: the fz domain; a β-strand

Full ROR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive Robinow syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: brachydactyly type B1

Similar variants

ROR2 p.Arg280Gln Uncertain significance ★ ⚠ same residue
ROR2 p.Arg280Trp 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-arg280leu (accessed [today's date]).

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