Is ROR2 p.Val821Ile (c.2461G>A) pathogenic?

ROR2 p.Val821Ile (c.2461G>A) is classified Conflicting classifications of pathogenicity in ROR2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-06). AlphaMissense: likely benign (0.1063); Rare (popmax 0.249%, afr).

How common is ROR2 p.Val821Ile (c.2461G>A) in the general population?

ROR2 p.Val821Ile (c.2461G>A) is rare (popmax 0.249%, afr) (gnomAD).

What do computational predictors say about ROR2 p.Val821Ile (c.2461G>A)?

AlphaMissense predicts likely benign (score 0.1063) — an in-silico prediction, not a clinical call.

ROR2 p.Val821Ile

c.2461G>A · rs149056068 · VCV500279

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1063 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.249%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1063	likely benign
REVEL	0.241	benign-leaning
SaProt	LLR -7.41	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 2.7	GERP -2, phastCons 0.99
Regional constraint	o/e 0.93	unconstrained · MANE · 226 kb · p 0.007 · regional, not allelic
Overall
CADD	22.8	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 0.249% African / African-American · 187/75,030 alleles

Filtering AF 0.22% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.209%

Overall 0.0145% 233/1,612,188 alleles · rare exomes 117/1,459,918 · genomes 116/152,270 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.249%	401
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.016%	6,248
Admixed American	0.0133%	7,500
East Asian	0.00223%	44,858
European (non-Finnish)	0.00212%	47,193
South Asian	0.0011%	91,062

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.Val821Ile
Coding: c.2461G>A
MANE Select: NM_004560
dbSNP: rs149056068
Type: single nucleotide variant
Location: chr9:91724033 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI 0.35 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 69.09 · 6 PDB

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

Similar variants

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
ROR2 c.*135G>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-val821ile (accessed [today's date]).

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