Is ROR1 p.Ala596Ser (c.1786G>T) pathogenic?

ROR1 p.Ala596Ser (c.1786G>T) is classified Uncertain significance in ROR1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-18). AlphaMissense: likely benign (0.0889); Ultra-rare (popmax 0.0657%, mid).

How common is ROR1 p.Ala596Ser (c.1786G>T) in the general population?

ROR1 p.Ala596Ser (c.1786G>T) is ultra-rare (popmax 0.0657%, mid) (gnomAD).

What do computational predictors say about ROR1 p.Ala596Ser (c.1786G>T)?

AlphaMissense predicts likely benign (score 0.0889) — an in-silico prediction, not a clinical call.

ROR1 p.Ala596Ser

c.1786G>T · rs774750393 · VCV1897929

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0889 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0657%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0889	likely benign
REVEL	0.264	benign-leaning
SaProt	LLR -8.55	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 12	GERP 5, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 129 kb · p 7e-13 · regional, not allelic
Overall
CADD	21.1	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 0.0657% Middle Eastern · 4/6,084 alleles

Filtering AF 0.0224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.0044% 71/1,614,056 alleles · ultra-rare exomes 66/1,461,866 · genomes 5/152,190 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0657%	1,521
European (non-Finnish)	0.00534%	18,731
Remaining individualsnot grpmax-eligible	0.0048%	20,829
Finnishnot grpmax-eligible	0.00156%	64,016

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.Ala596Ser
Coding: c.1786G>T
MANE Select: NM_005012
dbSNP: rs774750393
Type: single nucleotide variant
Location: chr1:64177827 (GRCh38)
Gene constraint: LOEUF 0.326 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.17 · 5 PDB
Residue 596: an α-helix; the protein kinase domain

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

Similar variants

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
ROR1 p.Arg474Cys Uncertain significance ★★ ⚠ same type
ROR1 p.Arg474His 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-ala596ser (accessed [today's date]).

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