Is ROR2 p.Ser557Leu (c.1670C>T) pathogenic?

ROR2 p.Ser557Leu (c.1670C>T) is classified Conflicting classifications of pathogenicity in ROR2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-08-25). AlphaMissense: likely benign (0.0781); Rare (popmax 0.122%, nfe); Associated with brachydactyly type B1.

What condition is associated with ROR2 p.Ser557Leu (c.1670C>T)?

ROR2 p.Ser557Leu (c.1670C>T) is associated with brachydactyly type B1, autosomal recessive Robinow syndrome (ClinVar).

How common is ROR2 p.Ser557Leu (c.1670C>T) in the general population?

ROR2 p.Ser557Leu (c.1670C>T) is rare (popmax 0.122%, nfe) (gnomAD).

What do computational predictors say about ROR2 p.Ser557Leu (c.1670C>T)?

AlphaMissense predicts likely benign (score 0.0781) — an in-silico prediction, not a clinical call.

ROR2 p.Ser557Leu

c.1670C>T · rs56099091 · VCV282760

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0781 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.122%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

brachydactyly type B1

Computational evidence

Protein change
AlphaMissense	0.0781	likely benign
REVEL	0.219	benign-leaning
SaProt	LLR -2.13	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP -0.55, phastCons 0.94
Regional constraint	o/e 0.93	unconstrained · MANE · 226 kb · p 0.007 · regional, not allelic
Overall
CADD	14.16	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 0.122% European (non-Finnish) · 1,433/1,175,194 alleles

Filtering AF 0.117% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.115%

Overall 0.102% 1,633/1,606,760 alleles · rare exomes 1,486/1,454,476 · genomes 147/152,284 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.768%	130
Finnishnot grpmax-eligible	0.126%	794
European (non-Finnish)grpmax	0.122%	820
Remaining individualsnot grpmax-eligible	0.0869%	1,151
Ashkenazi Jewishnot grpmax-eligible	0.0686%	1,458
African / African-American	0.0294%	3,406
Admixed American	0.0251%	3,991
East Asian	0.00223%	44,748
South Asian	0.00111%	90,196

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser557Leu
Coding: c.1670C>T
MANE Select: NM_004560
dbSNP: rs56099091
Type: single nucleotide variant
Location: chr9:91724824 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI 0.35 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 69.09 · 6 PDB
Residue 557: a UniProt-annotated variant site (in); the protein kinase 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 p.Ser557= Conflicting classifications of pathogenicity ★ 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-ser557leu (accessed [today's date]).

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