Is ROR2 p.Ser352Gly (c.1054A>G) pathogenic?

ROR2 p.Ser352Gly (c.1054A>G) is classified Conflicting classifications of pathogenicity in ROR2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-05-13). AlphaMissense: likely benign (0.0787); Ultra-rare (popmax 0.0713%, eas); Associated with autosomal recessive Robinow syndrome.

What condition is associated with ROR2 p.Ser352Gly (c.1054A>G)?

ROR2 p.Ser352Gly (c.1054A>G) is associated with autosomal recessive Robinow syndrome, brachydactyly type B1 (ClinVar).

How common is ROR2 p.Ser352Gly (c.1054A>G) in the general population?

ROR2 p.Ser352Gly (c.1054A>G) is ultra-rare (popmax 0.0713%, eas) (gnomAD).

What do computational predictors say about ROR2 p.Ser352Gly (c.1054A>G)?

AlphaMissense predicts likely benign (score 0.0787) — an in-silico prediction, not a clinical call.

ROR2 p.Ser352Gly

c.1054A>G · rs569242465 · VCV198514

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0787 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0713%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive Robinow syndrome

Computational evidence

Protein change
AlphaMissense	0.0787	likely benign
REVEL	0.102	moderately benign-leaning
SaProt	LLR -9.47	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.8	GERP -2.8, phastCons 0.98
Regional constraint	o/e 0.93	unconstrained · MANE · 226 kb · p 0.007 · regional, not allelic
Overall
CADD	19.78	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 0.0713% East Asian · 32/44,860 alleles

Filtering AF 0.0519% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0453%

Overall 0.00347% 56/1,614,146 alleles · ultra-rare exomes 50/1,461,878 · genomes 6/152,268 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0713%	1,402
Remaining individualsnot grpmax-eligible	0.0176%	5,683
South Asian	0.0143%	7,006

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.Ser352Gly
Coding: c.1054A>G
MANE Select: NM_004560
dbSNP: rs569242465
Type: single nucleotide variant
Location: chr9:91731039 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI 0.35 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 69.09 · 6 PDB
Residue 352: the kringle domain; a turn

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 p.Ser352Asn 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-ser352gly (accessed [today's date]).

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