Is ROR1 p.Arg474His (c.1421G>A) pathogenic?

ROR1 p.Arg474His (c.1421G>A) is classified Uncertain significance in ROR1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-09). AlphaMissense: ambiguous (0.4994); Ultra-rare (popmax 0.0481%, afr).

How common is ROR1 p.Arg474His (c.1421G>A) in the general population?

ROR1 p.Arg474His (c.1421G>A) is ultra-rare (popmax 0.0481%, afr) (gnomAD).

What do computational predictors say about ROR1 p.Arg474His (c.1421G>A)?

AlphaMissense predicts ambiguous (score 0.4994) — an in-silico prediction, not a clinical call.

ROR1 p.Arg474His

c.1421G>A · VCV3708010

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4994 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0481%, afr)

Computational evidence

Protein change
AlphaMissense	0.4994	ambiguous
REVEL	0.584	indeterminate
SaProt	LLR -6.37	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 4.7, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 129 kb · p 7e-13 · regional, not allelic
Overall
CADD	29.4	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 0.0481% African / African-American · 36/74,904 alleles

Filtering AF 0.0357% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0314%

Overall 0.00359% 58/1,613,928 alleles · ultra-rare exomes 34/1,461,826 · genomes 24/152,102 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0481%	2,081
Admixed American	0.0217%	4,615
Remaining individualsnot grpmax-eligible	0.0048%	20,828
South Asian	0.0022%	45,536
European (non-Finnish)	0.000339%	295,004

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.Arg474His
Coding: c.1421G>A
MANE Select: NM_005012
Type: single nucleotide variant
Location: chr1:64177462 (GRCh38)
Gene constraint: LOEUF 0.326 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.17 · 5 PDB
Residue 474: a β-strand; the protein kinase domain

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

Similar variants

ROR1 p.Arg474Cys Uncertain significance ★★ ⚠ same residue
ROR1 p.Ala596Ser Uncertain significance ★★ ⚠ same type
ROR1 p.Ala833Ser Uncertain significance ★★ ⚠ same type
ROR1 p.Ala923Gly Uncertain significance ★★ ⚠ same type
ROR1 p.Ala923Thr Uncertain significance ★★ ⚠ same type
ROR1 p.Ala935Val Uncertain significance ★★ ⚠ same type
ROR1 p.Arg25His Uncertain significance ★★ ⚠ same type
ROR1 p.Arg429Gln 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-arg474his (accessed [today's date]).

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