Is ROR2 p.Leu925Val (c.2773C>G) pathogenic?

ROR2 p.Leu925Val (c.2773C>G) is classified Uncertain significance in ROR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-14). AlphaMissense: ambiguous (0.3631); Very rare (popmax 0.00267%, afr); Associated with autosomal recessive Robinow syndrome.

What condition is associated with ROR2 p.Leu925Val (c.2773C>G)?

ROR2 p.Leu925Val (c.2773C>G) is associated with autosomal recessive Robinow syndrome, brachydactyly type B1 (ClinVar).

How common is ROR2 p.Leu925Val (c.2773C>G) in the general population?

ROR2 p.Leu925Val (c.2773C>G) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about ROR2 p.Leu925Val (c.2773C>G)?

AlphaMissense predicts ambiguous (score 0.3631) — an in-silico prediction, not a clinical call.

ROR2 p.Leu925Val

c.2773C>G · VCV3597712

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3631 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

autosomal recessive Robinow syndrome

Computational evidence

Protein change
AlphaMissense	0.3631	ambiguous
REVEL	0.269	benign-leaning
SaProt	LLR -6.20	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 0.54, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 226 kb · p 0.007 · regional, not allelic
Overall
CADD	22.6	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 0.00267% African / African-American · 2/74,936 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,613,840 alleles · very rare exomes 1/1,461,628 · genomes 1/152,212 · 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.Leu925Val
Coding: c.2773C>G
MANE Select: NM_004560
Type: single nucleotide variant
Location: chr9:91723721 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI 0.35 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 69.09 · 6 PDB
Residue 925: the 'disordered' region

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

Disease context

autosomal recessive Robinow syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: brachydactyly type B1

Similar variants

ROR2 c.175+1G>A Likely pathogenic ★★ same condition
ROR2 p.Arg119Ter Pathogenic ★★ same condition
ROR2 p.Arg397Ter Pathogenic ★★ same condition
ROR2 p.Arg442Ter Pathogenic ★★ same condition
ROR2 p.Arg528Ter Pathogenic/Likely pathogenic ★★ same condition
ROR2 c.175+3G>T Uncertain significance ★★ same condition
ROR2 c.-102G>T Uncertain significance ★★ same condition
ROR2 c.*135G>T 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-leu925val (accessed [today's date]).

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