Is ROR2 p.Ile270Val (c.808A>G) pathogenic?

ROR2 p.Ile270Val (c.808A>G) is classified Conflicting classifications of pathogenicity in ROR2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-02-05). AlphaMissense: likely benign (0.0872); Ultra-rare (popmax 0.017%, nfe); Associated with arthrogryposis multiplex congenita.

What condition is associated with ROR2 p.Ile270Val (c.808A>G)?

ROR2 p.Ile270Val (c.808A>G) is associated with arthrogryposis multiplex congenita, fetal akinesia deformation sequence 1 (ClinVar).

How common is ROR2 p.Ile270Val (c.808A>G) in the general population?

ROR2 p.Ile270Val (c.808A>G) is ultra-rare (popmax 0.017%, nfe) (gnomAD).

What do computational predictors say about ROR2 p.Ile270Val (c.808A>G)?

AlphaMissense predicts likely benign (score 0.0872) — an in-silico prediction, not a clinical call.

ROR2 p.Ile270Val

c.808A>G · rs145631389 · VCV498455

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0872 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.017%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

arthrogryposis multiplex congenita

Computational evidence

Protein change
AlphaMissense	0.0872	likely benign
REVEL	0.127	moderately benign-leaning
SaProt	LLR -5.75	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.1	GERP -3.2, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 226 kb · p 0.007 · regional, not allelic
Overall
CADD	19.57	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 0.017% European (non-Finnish) · 200/1,179,728 alleles

Filtering AF 0.015% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0143%

Overall 0.0134% 216/1,612,704 alleles · ultra-rare exomes 194/1,460,568 · genomes 22/152,136 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.017%	5,899
Admixed American	0.01%	9,988
Remaining individualsnot grpmax-eligible	0.00801%	12,488
African / African-American	0.00534%	18,725
Finnishnot grpmax-eligible	0.00158%	63,338

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.Ile270Val
Coding: c.808A>G
MANE Select: NM_004560
dbSNP: rs145631389
Type: single nucleotide variant
Location: chr9:91733251 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI 0.35 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 69.09 · 6 PDB
Residue 270: the fz domain; an α-helix

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

Disease context

arthrogryposis multiplex congenita — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: fetal akinesia deformation sequence 1

Similar variants

ROR2 p.Ile270= Likely benign ★ same residue
ROR2 p.Gly559Ser Conflicting classifications of pathogenicity ★ ⚠ same condition
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

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-ile270val (accessed [today's date]).

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