Is ROR2 p.Cys694Arg (c.2080T>C) pathogenic?

ROR2 p.Cys694Arg (c.2080T>C) is classified Conflicting classifications of pathogenicity in ROR2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-19). AlphaMissense: likely pathogenic (0.8973); Ultra-rare (popmax 0.0113%, nfe); Associated with brachydactyly type B1.

What condition is associated with ROR2 p.Cys694Arg (c.2080T>C)?

ROR2 p.Cys694Arg (c.2080T>C) is associated with brachydactyly type B1, autosomal recessive Robinow syndrome (ClinVar).

How common is ROR2 p.Cys694Arg (c.2080T>C) in the general population?

ROR2 p.Cys694Arg (c.2080T>C) is ultra-rare (popmax 0.0113%, nfe) (gnomAD).

What do computational predictors say about ROR2 p.Cys694Arg (c.2080T>C)?

AlphaMissense predicts likely pathogenic (score 0.8973) — an in-silico prediction, not a clinical call.

ROR2 p.Cys694Arg

c.2080T>C · rs142386992 · VCV199098

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.8973 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0113%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

brachydactyly type B1

Computational evidence

Protein change
AlphaMissense	0.8973	likely pathogenic
REVEL	0.761	pathogenic-leaning
SaProt	LLR -8.37	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 226 kb · p 0.007 · regional, not allelic
Overall
CADD	27.3	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 0.0113% European (non-Finnish) · 133/1,180,038 alleles

Filtering AF 0.00969% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00905%

Overall 0.00874% 141/1,614,074 alleles · ultra-rare exomes 137/1,461,858 · genomes 4/152,216 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0113%	8,872
Remaining individualsnot grpmax-eligible	0.008%	12,498
Admixed American	0.00333%	30,003
South Asian	0.0011%	91,094

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.Cys694Arg
Coding: c.2080T>C
MANE Select: NM_004560
dbSNP: rs142386992
Type: single nucleotide variant
Location: chr9:91724414 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI 0.35 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 69.09 · 6 PDB
Residue 694: the protein kinase domain; a turn

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-cys694arg (accessed [today's date]).

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