Is ROR2 p.Pro534His (c.1601C>A) pathogenic?

ROR2 p.Pro534His (c.1601C>A) is classified Uncertain significance in ROR2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-05). AlphaMissense: likely benign (0.1643); Ultra-rare (popmax 0.0585%, amr); Associated with brachydactyly type B1.

What condition is associated with ROR2 p.Pro534His (c.1601C>A)?

ROR2 p.Pro534His (c.1601C>A) is associated with brachydactyly type B1, autosomal recessive Robinow syndrome (ClinVar).

How common is ROR2 p.Pro534His (c.1601C>A) in the general population?

ROR2 p.Pro534His (c.1601C>A) is ultra-rare (popmax 0.0585%, amr) (gnomAD).

What do computational predictors say about ROR2 p.Pro534His (c.1601C>A)?

AlphaMissense predicts likely benign (score 0.1643) — an in-silico prediction, not a clinical call.

ROR2 p.Pro534His

c.1601C>A · rs762554351 · VCV1403084

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1643 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0585%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

brachydactyly type B1

Computational evidence

Protein change
AlphaMissense	0.1643	likely benign
REVEL	0.808	moderately pathogenic-leaning
SaProt	LLR -10.90	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 226 kb · p 0.007 · regional, not allelic
Overall
CADD	26.1	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 0.0585% Admixed American · 35/59,792 alleles

Filtering AF 0.0432% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0379%

Overall 0.00255% 41/1,606,380 alleles · ultra-rare exomes 38/1,454,154 · genomes 3/152,226 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0585%	1,708
European (non-Finnish)	0.000511%	195,762

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.Pro534His
Coding: c.1601C>A
MANE Select: NM_004560
dbSNP: rs762554351
Type: single nucleotide variant
Location: chr9:91724893 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI 0.35 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 69.09 · 6 PDB
Residue 534: the protein kinase 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-pro534his (accessed [today's date]).

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