Is ROR2 p.Pro878Ala (c.2632C>G) pathogenic?

ROR2 p.Pro878Ala (c.2632C>G) is classified Uncertain significance in ROR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-01). AlphaMissense: likely benign (0.3118); Ultra-rare (popmax 0.066%, mid); Associated with ROR2-related disorder.

What condition is associated with ROR2 p.Pro878Ala (c.2632C>G)?

ROR2 p.Pro878Ala (c.2632C>G) is associated with ROR2-related disorder (ClinVar).

How common is ROR2 p.Pro878Ala (c.2632C>G) in the general population?

ROR2 p.Pro878Ala (c.2632C>G) is ultra-rare (popmax 0.066%, mid) (gnomAD).

What do computational predictors say about ROR2 p.Pro878Ala (c.2632C>G)?

AlphaMissense predicts likely benign (score 0.3118) — an in-silico prediction, not a clinical call.

ROR2 p.Pro878Ala

c.2632C>G · rs1836888050 · VCV2636869

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3118 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.066%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

ROR2-related disorder

Computational evidence

Protein change
AlphaMissense	0.3118	likely benign
REVEL	0.401	indeterminate
SaProt	LLR -5.56	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.65, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 226 kb · p 0.007 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.066% Middle Eastern · 4/6,062 alleles

Filtering AF 0.0225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.000248% 4/1,614,060 alleles · ultra-rare exomes 4/1,461,742 · genomes 0/152,318 · joint denominator

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.Pro878Ala
Coding: c.2632C>G
MANE Select: NM_004560
dbSNP: rs1836888050
Type: single nucleotide variant
Location: chr9:91723862 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI 0.35 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 69.09 · 6 PDB
Residue 878: the 'disordered' region

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

Disease context

ROR2-related disorder

Similar variants

ROR2 p.Pro878His Uncertain significance ★★ ⚠ same residue
ROR2 p.Arg242His Uncertain significance ★★ ⚠ same condition
ROR2 p.Ser882Cys Uncertain significance ★★ same condition
ROR2 p.Arg657His Conflicting classifications of pathogenicity ★ ⚠ same condition
ROR2 p.Gln898His Conflicting classifications of pathogenicity ★ ⚠ same condition
ROR2 p.Gln910Arg Uncertain significance ★ ⚠ same condition
ROR2 p.Pro810Leu Uncertain significance ★ ⚠ same condition
ROR2 p.Ser762Leu Conflicting classifications of pathogenicity ★ ⚠ 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-pro878ala (accessed [today's date]).

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