Is ROR2 p.Val819Ile (c.2455G>A) pathogenic?

ROR2 p.Val819Ile (c.2455G>A) is classified Benign in ROR2 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0443); Common (popmax 94.4%, eas) — too common for a highly-penetrant pathogenic allele; Associated with autosomal dominant Robinow syndrome 1.

What condition is associated with ROR2 p.Val819Ile (c.2455G>A)?

ROR2 p.Val819Ile (c.2455G>A) is associated with autosomal dominant Robinow syndrome 1, brachydactyly type B1, autosomal recessive Robinow syndrome (ClinVar).

What do computational predictors say about ROR2 p.Val819Ile (c.2455G>A)?

AlphaMissense predicts likely benign (score 0.0443) — an in-silico prediction, not a clinical call.

ROR2 p.Val819Ile

Q: How common is ROR2 p.Val819Ile (c.2455G>A) in the general population?

ROR2 p.Val819Ile (c.2455G>A) is common (popmax 94.4%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2455G>A · rs10761129 · VCV159818

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.0443 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 94.4%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal dominant Robinow syndrome 1

Computational evidence

Protein change
AlphaMissense	0.0443	likely benign
REVEL	0.238	benign-leaning
SaProt	LLR -7.28	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 4.2	GERP 0.85, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 226 kb · p 0.007 · regional, not allelic
Overall
CADD	15.69	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 94.4% East Asian · 42,315/44,848 alleles

Filtering AF 93.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 93.3%

Overall 68.7% 1,106,698/1,611,526 alleles · common exomes 997,906/1,459,400 · genomes 108,792/152,126 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	94.4%	1
Admixed American	82%	1
African / African-American	76%	1
Finnishnot grpmax-eligible	73.7%	1
Remaining individualsnot grpmax-eligible	68.8%	1
European (non-Finnish)	67%	1
Amishnot grpmax-eligible	67%	1
Middle Eastern	64.6%	2
South Asian	61.6%	2
Ashkenazi Jewishnot grpmax-eligible	61.2%	2

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.Val819Ile
Coding: c.2455G>A
MANE Select: NM_004560
dbSNP: rs10761129
Type: single nucleotide variant
Location: chr9:91724039 (GRCh38)
Gene constraint: LOEUF 0.543 · pLI 0.35 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 69.09 · 6 PDB
Residue 819: a UniProt-annotated variant site (in)

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

Disease context

autosomal dominant Robinow syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: brachydactyly type B1 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-val819ile (accessed [today's date]).

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