Is ROR1 p.Phe688Leu (c.2064T>G) pathogenic?

ROR1 p.Phe688Leu (c.2064T>G) is classified Uncertain significance in ROR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-02). AlphaMissense: likely pathogenic (0.9756); Ultra-rare (popmax 0.0231%, nfe).

How common is ROR1 p.Phe688Leu (c.2064T>G) in the general population?

ROR1 p.Phe688Leu (c.2064T>G) is ultra-rare (popmax 0.0231%, nfe) (gnomAD).

What do computational predictors say about ROR1 p.Phe688Leu (c.2064T>G)?

AlphaMissense predicts likely pathogenic (score 0.9756) — an in-silico prediction, not a clinical call.

ROR1 p.Phe688Leu

c.2064T>G · VCV3641129

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9756 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0231%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9756	likely pathogenic
REVEL	0.243	benign-leaning
SaProt	LLR -7.48	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.1	GERP -4.9
Regional constraint	o/e 0.78	unconstrained · MANE · 129 kb · p 7e-13 · regional, not allelic
Overall
CADD	17.89	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 0.0231% European (non-Finnish) · 272/1,180,030 alleles

Filtering AF 0.0208% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0199%

Overall 0.0179% 289/1,614,180 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0231%	4,338
Remaining individualsnot grpmax-eligible	0.0112%	8,930
African / African-American	0.00933%	10,718
Admixed American	0.005%	20,009

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.Phe688Leu
Coding: c.2064T>G
MANE Select: NM_005012
Type: single nucleotide variant
Location: chr1:64178105 (GRCh38)
Gene constraint: LOEUF 0.326 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 69.17 · 5 PDB
Residue 688: the protein kinase domain

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

Similar variants

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
ROR1 p.Arg474Cys 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-phe688leu (accessed [today's date]).

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