Is ROR1 p.Val451= (c.1353A>G) pathogenic?

ROR1 p.Val451= (c.1353A>G) is classified Benign in ROR1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-03). Common (popmax 43.4%, eas) — too common for a highly-penetrant pathogenic allele; Associated with hearing loss, autosomal recessive 108.

What condition is associated with ROR1 p.Val451= (c.1353A>G)?

ROR1 p.Val451= (c.1353A>G) is associated with hearing loss, autosomal recessive 108 (ClinVar).

ROR1 p.Val451=

Q: How common is ROR1 p.Val451= (c.1353A>G) in the general population?

ROR1 p.Val451= (c.1353A>G) is common (popmax 43.4%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1353A>G · rs6668545 · VCV1260721

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Common

common (popmax 43.4%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

hearing loss, autosomal recessive 108

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.25	donor gain, 33 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP -1.4	GERP -5.1
Overall
CADD	4.188	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 43.4% East Asian · 19,454/44,860 alleles

Filtering AF 42.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 42.6%

Overall 35.5% 573,355/1,613,362 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	43.4%	2
Middle Eastern	39.3%	3
South Asian	38.8%	3
Admixed American	37.8%	3
Remaining individualsnot grpmax-eligible	36.4%	3
Finnishnot grpmax-eligible	36.2%	3
Ashkenazi Jewishnot grpmax-eligible	35.8%	3
European (non-Finnish)	35.6%	3
Amishnot grpmax-eligible	26.4%	4
African / African-American	22.8%	4

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: ROR1
Protein: p.Val451=
Coding: c.1353A>G
MANE Select: NM_005012
dbSNP: rs6668545
Type: single nucleotide variant
Location: chr1:64159159 (GRCh38)
Gene constraint: LOEUF 0.326 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.17 · 5 PDB

Full ROR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hearing loss, autosomal recessive 108 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ROR1 p.Pro547Ser Uncertain significance ★★ ⚠ same condition
ROR1 p.Ala390= Benign ★★ same condition
ROR1 p.Leu60= Benign ★★ same condition
ROR1 p.Thr518Met Benign ★★ same condition
ROR1 p.Glu452Asp Conflicting classifications of pathogenicity ★ ⚠ same condition
ROR1 p.Tyr910Asp Uncertain significance ★ ⚠ same condition
ROR1 p.Ala596Ser Uncertain significance ★★ ⚠ same type
ROR1 p.Ala833Ser Uncertain significance ★★ ⚠ same type

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/ror1-p-val451 (accessed [today's date]).

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