Is CABLES2 p.Arg45Leu (c.134G>T) pathogenic?

CABLES2 p.Arg45Leu (c.134G>T) is classified Uncertain significance in CABLES2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-22). AlphaMissense: likely pathogenic (0.9627); Rare (popmax 0.263%, amr).

How common is CABLES2 p.Arg45Leu (c.134G>T) in the general population?

CABLES2 p.Arg45Leu (c.134G>T) is rare (popmax 0.263%, amr) (gnomAD).

What do computational predictors say about CABLES2 p.Arg45Leu (c.134G>T)?

AlphaMissense predicts likely pathogenic (score 0.9627) — an in-silico prediction, not a clinical call.

CABLES2 p.Arg45Leu

c.134G>T · rs868316661 · VCV2348420

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9627 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.263%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9627	likely pathogenic
REVEL	0.415	indeterminate
SaProt	LLR -4.93	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 0.62, phastCons 1
Regional constraint	o/e 1.64	unconstrained · MANE · 225 bp · p 1.3e-08 · regional, not allelic
Overall
CADD	21.8	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 0.263% Admixed American · 46/17,494 alleles

Filtering AF 0.202% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.181%

Overall 0.00657% 67/1,019,574 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.263%	380
Ashkenazi Jewishnot grpmax-eligible	0.031%	3,225
Remaining individualsnot grpmax-eligible	0.0255%	3,928
African / African-American	0.00523%	19,139
South Asian	0.00432%	23,170
European (non-Finnish)	0.000705%	141,877

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: CABLES2
Protein: p.Arg45Leu
Coding: c.134G>T
MANE Select: NM_031215
dbSNP: rs868316661
Type: single nucleotide variant
Location: chr20:62407143 (GRCh38)
Gene constraint: LOEUF 1 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.39
Residue 45: the 'disordered' region

Full CABLES2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CABLES2 p.Arg128His Uncertain significance ★★ ⚠ same type
CABLES2 p.Leu103= Benign ★★ same type
CABLES2 p.Ala13Asp Uncertain significance ★ ⚠ same type
CABLES2 p.Ala17Thr Uncertain significance ★ ⚠ same type
CABLES2 p.Ala23Asp Uncertain significance ★ ⚠ same type
CABLES2 p.Ala23Thr Uncertain significance ★ ⚠ same type
CABLES2 p.Ala287Val Uncertain significance ★ ⚠ same type
CABLES2 p.Ala35Val 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/cables2-p-arg45leu (accessed [today's date]).

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