Is ROR2 p.Ile180Val (c.538A>G) pathogenic?

ROR2 p.Ile180Val (c.538A>G) is classified Benign in ROR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-14). AlphaMissense: likely benign (0.1469); Rare (popmax 0.614%, sas).

How common is ROR2 p.Ile180Val (c.538A>G) in the general population?

ROR2 p.Ile180Val (c.538A>G) is rare (popmax 0.614%, sas) (gnomAD).

What do computational predictors say about ROR2 p.Ile180Val (c.538A>G)?

AlphaMissense predicts likely benign (score 0.1469) — an in-silico prediction, not a clinical call.

ROR2 p.Ile180Val

c.538A>G · rs553341457 · VCV1550446

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1469 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.614%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1469	likely benign
REVEL	0.177	moderately benign-leaning
SaProt	LLR -5.18	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 6.2	GERP 2.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 226 kb · p 0.007 · regional, not allelic
Overall
CADD	22.3	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 0.614% South Asian · 559/91,086 alleles

Filtering AF 0.572% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.555%

Overall 0.036% 581/1,614,198 alleles · rare exomes 557/1,461,880 · genomes 24/152,318 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.614%	163
Remaining individualsnot grpmax-eligible	0.0224%	4,465
European (non-Finnish)	0.000678%	147,505

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.Ile180Val
Coding: c.538A>G
MANE Select: NM_004560
dbSNP: rs553341457
Type: single nucleotide variant
Location: chr9:91737475 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI 0.35 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 69.09 · 6 PDB
Residue 180: the fz domain

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-ile180val (accessed [today's date]).

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