Is ROR2 p.Val542Met (c.1624G>A) pathogenic?

ROR2 p.Val542Met (c.1624G>A) is classified Uncertain significance in ROR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-10). AlphaMissense: likely benign (0.0888); Ultra-rare (popmax 0.0166%, mid); Associated with brachydactyly type B1.

What condition is associated with ROR2 p.Val542Met (c.1624G>A)?

ROR2 p.Val542Met (c.1624G>A) is associated with brachydactyly type B1, autosomal recessive Robinow syndrome (ClinVar).

How common is ROR2 p.Val542Met (c.1624G>A) in the general population?

ROR2 p.Val542Met (c.1624G>A) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about ROR2 p.Val542Met (c.1624G>A)?

AlphaMissense predicts likely benign (score 0.0888) — an in-silico prediction, not a clinical call.

ROR2 p.Val542Met

c.1624G>A · rs140213020 · VCV1407886

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0888 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

brachydactyly type B1

Computational evidence

Protein change
AlphaMissense	0.0888	likely benign
REVEL	0.451	indeterminate
SaProt	LLR -10.92	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.5	GERP -1.2
Regional constraint	o/e 0.93	unconstrained · MANE · 226 kb · p 0.007 · regional, not allelic
Overall
CADD	14.78	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 0.0166% Middle Eastern · 1/6,026 alleles

Filtering AF 0.00566% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00518%

Overall 0.00574% 92/1,601,798 alleles · ultra-rare exomes 77/1,449,592 · genomes 15/152,206 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0166%	6,026
European (non-Finnish)	0.00691%	14,471
Admixed American	0.00503%	19,867
Remaining individualsnot grpmax-eligible	0.00485%	20,625
Ashkenazi Jewishnot grpmax-eligible	0.00346%	28,884
African / African-American	0.00268%	37,353
South Asian	0.00112%	89,530

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.Val542Met
Coding: c.1624G>A
MANE Select: NM_004560
dbSNP: rs140213020
Type: single nucleotide variant
Location: chr9:91724870 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI 0.35 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 69.09 · 6 PDB
Residue 542: a UniProt-annotated variant site (in a colorectal adenocarcinoma sample; somatic mutation); the protein kinase domain; a β-strand

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

Disease context

brachydactyly type B1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive Robinow syndrome

Similar variants

ROR2 p.Val542Leu Uncertain significance ★ ⚠ same residue
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

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-val542met (accessed [today's date]).

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