Is ROR2 p.Pro275Leu (c.824C>T) pathogenic?

ROR2 p.Pro275Leu (c.824C>T) is classified Uncertain significance in ROR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-19). AlphaMissense: likely pathogenic (0.7952); Very rare (popmax 0.00161%, nfe).

How common is ROR2 p.Pro275Leu (c.824C>T) in the general population?

ROR2 p.Pro275Leu (c.824C>T) is very rare (popmax 0.00161%, nfe) (gnomAD).

What do computational predictors say about ROR2 p.Pro275Leu (c.824C>T)?

AlphaMissense predicts likely pathogenic (score 0.7952) — an in-silico prediction, not a clinical call.

ROR2 p.Pro275Leu

c.824C>T · rs752527875 · VCV1918908

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7952 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7952	likely pathogenic
REVEL	0.827	moderately pathogenic-leaning
SaProt	LLR -9.05	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 226 kb · p 0.007 · regional, not allelic
Overall
CADD	32.0	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 0.00161% European (non-Finnish) · 19/1,179,700 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.00136% 22/1,612,548 alleles · very rare exomes 21/1,460,332 · genomes 1/152,216 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00481%	20,809
European (non-Finnish)grpmax	0.00161%	62,089

Remaining individuals 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.Pro275Leu
Coding: c.824C>T
MANE Select: NM_004560
dbSNP: rs752527875
Type: single nucleotide variant
Location: chr9:91733235 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI 0.35 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 69.09 · 6 PDB
Residue 275: the fz domain; an α-helix

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

Similar variants

ROR2 p.Pro275= Likely benign ★ 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-pro275leu (accessed [today's date]).

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