Is ROR2 p.Phe686Leu (c.2058C>A) pathogenic?

ROR2 p.Phe686Leu (c.2058C>A) is classified Uncertain significance in ROR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-15). AlphaMissense: likely pathogenic (0.99); Very rare (popmax 0.000254%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ROR2 p.Phe686Leu (c.2058C>A)?

ROR2 p.Phe686Leu (c.2058C>A) is associated with Inborn genetic diseases (ClinVar).

How common is ROR2 p.Phe686Leu (c.2058C>A) in the general population?

ROR2 p.Phe686Leu (c.2058C>A) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about ROR2 p.Phe686Leu (c.2058C>A)?

AlphaMissense predicts likely pathogenic (score 0.99) — an in-silico prediction, not a clinical call.

ROR2 p.Phe686Leu

c.2058C>A · rs191107364 · VCV2210810

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.99 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.99	likely pathogenic · top 7% in ROR2
REVEL	0.753	pathogenic-leaning
SaProt	LLR -9.27	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.3	GERP 0.91, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 226 kb · p 0.007 · regional, not allelic
Overall
CADD	24.1	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 0.000254% European (non-Finnish) · 3/1,180,036 alleles

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

Overall 0.000681% 11/1,614,216 alleles · very rare exomes 9/1,461,862 · genomes 2/152,354 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0109%	9,147
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)grpmax	0.000254%	393,345

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.Phe686Leu
Coding: c.2058C>A
MANE Select: NM_004560
dbSNP: rs191107364
Type: single nucleotide variant
Location: chr9:91724436 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI 0.35 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 69.09 · 6 PDB
Residue 686: the protein kinase domain; an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ROR2 p.Ala241Val Uncertain significance ★★ ⚠ same condition
ROR2 p.Ala288Val Uncertain significance ★★ ⚠ same condition
ROR2 p.Ala513Val Uncertain significance ★★ ⚠ same condition
ROR2 p.Ala597Val Uncertain significance ★★ ⚠ same condition
ROR2 p.Ala601Thr Uncertain significance ★★ ⚠ same condition
ROR2 p.Arg107Trp Uncertain significance ★★ same condition
ROR2 p.Arg153Trp Uncertain significance ★★ ⚠ same condition
ROR2 p.Arg178Gln 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-phe686leu (accessed [today's date]).

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