Is ROR2 p.Pro712Ser (c.2134C>T) pathogenic?

ROR2 p.Pro712Ser (c.2134C>T) is classified Uncertain significance in ROR2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-07-01). AlphaMissense: likely benign (0.1096); Ultra-rare (popmax 0.024%, afr); Associated with Inborn genetic diseases.

What condition is associated with ROR2 p.Pro712Ser (c.2134C>T)?

ROR2 p.Pro712Ser (c.2134C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ROR2 p.Pro712Ser (c.2134C>T) in the general population?

ROR2 p.Pro712Ser (c.2134C>T) is ultra-rare (popmax 0.024%, afr) (gnomAD).

What do computational predictors say about ROR2 p.Pro712Ser (c.2134C>T)?

AlphaMissense predicts likely benign (score 0.1096) — an in-silico prediction, not a clinical call.

ROR2 p.Pro712Ser

c.2134C>T · rs374945194 · VCV2722020

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1096 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.024%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1096	likely benign
REVEL	0.318	indeterminate
SaProt	LLR -8.55	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 226 kb · p 0.007 · regional, not allelic
Overall
CADD	20.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.024% African / African-American · 18/74,944 alleles

Filtering AF 0.0155% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0128%

Overall 0.00167% 27/1,613,676 alleles · ultra-rare exomes 17/1,461,452 · genomes 10/152,224 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.024%	4,164
Remaining individualsnot grpmax-eligible	0.008%	12,496
South Asian	0.00439%	22,773

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.Pro712Ser
Coding: c.2134C>T
MANE Select: NM_004560
dbSNP: rs374945194
Type: single nucleotide variant
Location: chr9:91724360 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI 0.35 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 69.09 · 6 PDB
Residue 712: the protein kinase domain; an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ROR2 p.Pro712Leu Uncertain significance ★ ⚠ same residue
ROR2 p.Ala241Val Uncertain significance ★★ ⚠ same condition
ROR2 p.Ala288Val Uncertain significance ★★ ⚠ same condition
ROR2 p.Ala513Val Uncertain significance ★★ ⚠ same condition
ROR2 p.Ala597Val Uncertain significance ★★ ⚠ same condition
ROR2 p.Ala601Thr Uncertain significance ★★ ⚠ same condition
ROR2 p.Arg107Trp Uncertain significance ★★ same condition
ROR2 p.Arg153Trp 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-pro712ser (accessed [today's date]).

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