Is ROR2 p.Asp221Glu (c.663C>G) pathogenic?

ROR2 p.Asp221Glu (c.663C>G) is classified Uncertain significance in ROR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-17). AlphaMissense: ambiguous (0.4212); Very rare (popmax 0.00801%, afr); Associated with brachydactyly type B1.

What condition is associated with ROR2 p.Asp221Glu (c.663C>G)?

ROR2 p.Asp221Glu (c.663C>G) is associated with brachydactyly type B1, autosomal recessive Robinow syndrome (ClinVar).

How common is ROR2 p.Asp221Glu (c.663C>G) in the general population?

ROR2 p.Asp221Glu (c.663C>G) is very rare (popmax 0.00801%, afr) (gnomAD).

What do computational predictors say about ROR2 p.Asp221Glu (c.663C>G)?

AlphaMissense predicts ambiguous (score 0.4212) — an in-silico prediction, not a clinical call.

ROR2 p.Asp221Glu

c.663C>G · rs1461699343 · VCV1384746

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4212 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

brachydactyly type B1

Computational evidence

Protein change
AlphaMissense	0.4212	ambiguous
REVEL	0.252	benign-leaning
SaProt	LLR -6.15	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 3.2	GERP 0.7, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 226 kb · p 0.007 · regional, not allelic
Overall
CADD	23.2	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 · 6/74,942 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00228%

Overall 0.000372% 6/1,611,778 alleles · very rare exomes 2/1,459,548 · genomes 4/152,230 · 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.Asp221Glu
Coding: c.663C>G
MANE Select: NM_004560
dbSNP: rs1461699343
Type: single nucleotide variant
Location: chr9:91733396 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI 0.35 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 69.09 · 6 PDB
Residue 221: an α-helix; the fz domain

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-asp221glu (accessed [today's date]).

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