Is ROR1 p.Pro547Ser (c.1639C>T) pathogenic?

ROR1 p.Pro547Ser (c.1639C>T) is classified Uncertain significance in ROR1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-14). AlphaMissense: likely pathogenic (0.9606); Ultra-rare (popmax 0.045%, amr); Associated with hearing loss, autosomal recessive 108.

What condition is associated with ROR1 p.Pro547Ser (c.1639C>T)?

ROR1 p.Pro547Ser (c.1639C>T) is associated with hearing loss, autosomal recessive 108 (ClinVar).

How common is ROR1 p.Pro547Ser (c.1639C>T) in the general population?

ROR1 p.Pro547Ser (c.1639C>T) is ultra-rare (popmax 0.045%, amr) (gnomAD).

What do computational predictors say about ROR1 p.Pro547Ser (c.1639C>T)?

AlphaMissense predicts likely pathogenic (score 0.9606) — an in-silico prediction, not a clinical call.

ROR1 p.Pro547Ser

c.1639C>T · rs137874089 · VCV1424363

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9606 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.045%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hearing loss, autosomal recessive 108

Computational evidence

Protein change
AlphaMissense	0.9606	likely pathogenic
REVEL	0.706	pathogenic-leaning
SaProt	LLR -12.43	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 5, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 129 kb · p 7e-13 · regional, not allelic
Overall
CADD	25.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.045% Admixed American · 27/60,012 alleles

Filtering AF 0.0317% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0273%

Overall 0.00706% 114/1,614,084 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.045%	2,223
Middle Eastern	0.0329%	3,042
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,869
European (non-Finnish)	0.00636%	15,734
Remaining individualsnot grpmax-eligible	0.0048%	20,829
African / African-American	0.004%	24,972
South Asian	0.0011%	91,082

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.Pro547Ser
Coding: c.1639C>T
MANE Select: NM_005012
dbSNP: rs137874089
Type: single nucleotide variant
Location: chr1:64177680 (GRCh38)
Gene constraint: LOEUF 0.326 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.17 · 5 PDB
Residue 547: a β-strand; the protein kinase domain

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.Pro547Arg Uncertain significance ★ ⚠ same residue
ROR1 p.Ala390= Benign ★★ same condition
ROR1 p.Leu60= Benign ★★ same condition
ROR1 p.Thr518Met Benign ★★ same condition
ROR1 p.Val451= 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

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-pro547ser (accessed [today's date]).

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