Is ROR2 p.Leu549Pro (c.1646T>C) pathogenic?

ROR2 p.Leu549Pro (c.1646T>C) is classified Uncertain significance in ROR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-16). AlphaMissense: likely benign (0.3324); Very rare (popmax 0.00134%, afr).

How common is ROR2 p.Leu549Pro (c.1646T>C) in the general population?

ROR2 p.Leu549Pro (c.1646T>C) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about ROR2 p.Leu549Pro (c.1646T>C)?

AlphaMissense predicts likely benign (score 0.3324) — an in-silico prediction, not a clinical call.

ROR2 p.Leu549Pro

c.1646T>C · rs756321168 · VCV2903149

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3324 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3324	likely benign
REVEL	0.667	pathogenic-leaning
SaProt	LLR -10.61	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 8	GERP 0.85, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 226 kb · p 0.007 · regional, not allelic
Overall
CADD	24.8	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 0.00134% African / African-American · 1/74,892 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000249% 4/1,603,444 alleles · very rare exomes 4/1,451,134 · genomes 0/152,310 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,892
European (non-Finnish)	0.000256%	391,083

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.Leu549Pro
Coding: c.1646T>C
MANE Select: NM_004560
dbSNP: rs756321168
Type: single nucleotide variant
Location: chr9:91724848 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI 0.35 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 69.09 · 6 PDB
Residue 549: the protein kinase domain

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

Similar variants

ROR2 p.Leu549= Likely benign ★ same residue
ROR2 c.175+1G>A Likely pathogenic ★★ same type
ROR2 p.Arg119Ter Pathogenic ★★ same type
ROR2 p.Arg397Ter Pathogenic ★★ same type
ROR2 p.Arg442Ter Pathogenic ★★ same type
ROR2 p.Arg528Ter Pathogenic/Likely pathogenic ★★ same type
ROR2 c.175+3G>T Uncertain significance ★★ same type
ROR2 c.-102G>T Uncertain significance ★★ same type

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-leu549pro (accessed [today's date]).

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