Is ROR2 p.Pro497Leu (c.1490C>T) pathogenic?

ROR2 p.Pro497Leu (c.1490C>T) is classified Uncertain significance in ROR2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-03-21). AlphaMissense: likely benign (0.0783); Ultra-rare (popmax 0.0183%, amr); Associated with brachydactyly type B1.

What condition is associated with ROR2 p.Pro497Leu (c.1490C>T)?

ROR2 p.Pro497Leu (c.1490C>T) is associated with brachydactyly type B1, autosomal recessive Robinow syndrome (ClinVar).

How common is ROR2 p.Pro497Leu (c.1490C>T) in the general population?

ROR2 p.Pro497Leu (c.1490C>T) is ultra-rare (popmax 0.0183%, amr) (gnomAD).

What do computational predictors say about ROR2 p.Pro497Leu (c.1490C>T)?

AlphaMissense predicts likely benign (score 0.0783) — an in-silico prediction, not a clinical call.

ROR2 p.Pro497Leu

c.1490C>T · rs772631240 · VCV499901

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0783 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0183%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

brachydactyly type B1

Computational evidence

Protein change
AlphaMissense	0.0783	likely benign
REVEL	0.573	indeterminate
SaProt	LLR -10.76	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP -1.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 226 kb · p 0.007 · regional, not allelic
Overall
CADD	22.7	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 0.0183% Admixed American · 11/60,008 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00785%

Overall 0.00273% 44/1,613,650 alleles · ultra-rare exomes 32/1,461,456 · genomes 12/152,194 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0267%	3,742
Admixed Americangrpmax	0.0183%	5,455
South Asian	0.0022%	45,543
Remaining individualsnot grpmax-eligible	0.0016%	62,482
European (non-Finnish)	0.0011%	90,771

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.Pro497Leu
Coding: c.1490C>T
MANE Select: NM_004560
dbSNP: rs772631240
Type: single nucleotide variant
Location: chr9:91725004 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI 0.35 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 69.09 · 6 PDB
Residue 497: 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 p.Pro497= Conflicting classifications of pathogenicity ★ same residue
ROR2 p.Pro497Gln 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-pro497leu (accessed [today's date]).

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