Is ROR2 p.Asp591Asn (c.1771G>A) pathogenic?

ROR2 p.Asp591Asn (c.1771G>A) is classified Uncertain significance in ROR2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-21). AlphaMissense: ambiguous (0.4097); Very rare (popmax 0.00801%, afr); Associated with brachydactyly type B1.

What condition is associated with ROR2 p.Asp591Asn (c.1771G>A)?

ROR2 p.Asp591Asn (c.1771G>A) is associated with brachydactyly type B1, autosomal recessive Robinow syndrome (ClinVar).

How common is ROR2 p.Asp591Asn (c.1771G>A) in the general population?

ROR2 p.Asp591Asn (c.1771G>A) is very rare (popmax 0.00801%, afr) (gnomAD).

What do computational predictors say about ROR2 p.Asp591Asn (c.1771G>A)?

AlphaMissense predicts ambiguous (score 0.4097) — an in-silico prediction, not a clinical call.

ROR2 p.Asp591Asn

c.1771G>A · rs768175141 · VCV1399575

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4097 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Conditions

brachydactyly type B1

Computational evidence

Protein change
AlphaMissense	0.4097	ambiguous
REVEL	0.641	indeterminate
SaProt	LLR -9.94	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 226 kb · p 0.007 · regional, not allelic
Overall
CADD	25.0	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 0.00801% African / African-American · 6/74,924 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00252%

Overall 0.0039% 63/1,614,014 alleles · very rare exomes 58/1,461,828 · genomes 5/152,186 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00801%	12,487
Admixed American	0.005%	20,002
East Asian	0.00446%	22,442
South Asian	0.00439%	22,771
European (non-Finnish)	0.00373%	26,819
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
Remaining individualsnot grpmax-eligible	0.0032%	31,245
Finnishnot grpmax-eligible	0.00156%	63,972

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.Asp591Asn
Coding: c.1771G>A
MANE Select: NM_004560
dbSNP: rs768175141
Type: single nucleotide variant
Location: chr9:91724723 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI 0.35 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 69.09 · 6 PDB
Residue 591: the protein kinase domain; an α-helix

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 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-asp591asn (accessed [today's date]).

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