Is ROR2 p.Pro548Ser (c.1642C>T) pathogenic?

ROR2 p.Pro548Ser (c.1642C>T) is classified Benign in ROR2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-22). AlphaMissense: likely pathogenic (0.9171); Low-frequency (popmax 3.97%, afr); Associated with autosomal recessive Robinow syndrome.

What condition is associated with ROR2 p.Pro548Ser (c.1642C>T)?

ROR2 p.Pro548Ser (c.1642C>T) is associated with autosomal recessive Robinow syndrome, brachydactyly type B1 (ClinVar).

How common is ROR2 p.Pro548Ser (c.1642C>T) in the general population?

ROR2 p.Pro548Ser (c.1642C>T) is low-frequency (popmax 3.97%, afr) (gnomAD).

What do computational predictors say about ROR2 p.Pro548Ser (c.1642C>T)?

AlphaMissense predicts likely pathogenic (score 0.9171) — an in-silico prediction, not a clinical call.

ROR2 p.Pro548Ser

c.1642C>T · rs35764413 · VCV367502

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9171 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 3.97%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive Robinow syndrome

Computational evidence

Protein change
AlphaMissense	0.9171	likely pathogenic
REVEL	0.727	pathogenic-leaning
SaProt	LLR -13.80	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
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	27.2	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 3.97% African / African-American · 2,969/74,846 alleles

Filtering AF 3.85% ClinGen BA1/BS1 input FAF95, joint · FAF99 3.8%

Overall 0.209% 3,346/1,602,716 alleles · low-frequency exomes 1,669/1,450,394 · genomes 1,677/152,322 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.97%	25
Admixed American	0.286%	349
Remaining individualsnot grpmax-eligible	0.255%	392
Middle Eastern	0.0666%	1,503
South Asian	0.00671%	14,909
European (non-Finnish)	0.00324%	30,864

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.Pro548Ser
Coding: c.1642C>T
MANE Select: NM_004560
dbSNP: rs35764413
Type: single nucleotide variant
Location: chr9:91724852 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI 0.35 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 69.09 · 6 PDB
Residue 548: a UniProt-annotated variant site (in); the protein kinase 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.Pro548= 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
ROR2 c.-102G>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-pro548ser (accessed [today's date]).

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