Is ROR2 p.Ala586Val (c.1757C>T) pathogenic?

ROR2 p.Ala586Val (c.1757C>T) is classified Uncertain significance in ROR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-27). AlphaMissense: likely benign (0.0873); Ultra-rare (popmax 0.0513%, eas).

How common is ROR2 p.Ala586Val (c.1757C>T) in the general population?

ROR2 p.Ala586Val (c.1757C>T) is ultra-rare (popmax 0.0513%, eas) (gnomAD).

What do computational predictors say about ROR2 p.Ala586Val (c.1757C>T)?

AlphaMissense predicts likely benign (score 0.0873) — an in-silico prediction, not a clinical call.

ROR2 p.Ala586Val

c.1757C>T · rs763556461 · VCV1363045

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0873 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0513%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0873	likely benign
REVEL	0.222	benign-leaning
SaProt	LLR -4.25	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 0.78, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 226 kb · p 0.007 · regional, not allelic
Overall
CADD	17.53	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0513% East Asian · 23/44,870 alleles

Filtering AF 0.035% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0296%

Overall 0.00173% 28/1,614,124 alleles · ultra-rare exomes 23/1,461,792 · genomes 5/152,332 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0513%	1,951
Remaining individualsnot grpmax-eligible	0.0032%	31,256
South Asian	0.0022%	45,541
European (non-Finnish)	8.47e-05%	1,180,038

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.Ala586Val
Coding: c.1757C>T
MANE Select: NM_004560
dbSNP: rs763556461
Type: single nucleotide variant
Location: chr9:91724737 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI 0.35 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 69.09 · 6 PDB
Residue 586: the protein kinase domain

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

Similar variants

ROR2 p.Ala586Thr Conflicting classifications of pathogenicity ★ ⚠ 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-ala586val (accessed [today's date]).

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