Is CABLES2 p.Pro12Arg (c.35C>G) pathogenic?

CABLES2 p.Pro12Arg (c.35C>G) is classified Uncertain significance in CABLES2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-01). AlphaMissense: likely benign (0.1064); Ultra-rare (popmax 0.0387%, eas).

How common is CABLES2 p.Pro12Arg (c.35C>G) in the general population?

CABLES2 p.Pro12Arg (c.35C>G) is ultra-rare (popmax 0.0387%, eas) (gnomAD).

What do computational predictors say about CABLES2 p.Pro12Arg (c.35C>G)?

AlphaMissense predicts likely benign (score 0.1064) — an in-silico prediction, not a clinical call.

CABLES2 p.Pro12Arg

c.35C>G · rs1250790930 · VCV2388102

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1064 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0387%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1064	likely benign
REVEL	0.041	moderately benign-leaning
SaProt	LLR -8.34	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 1.1	GERP -0.77
Regional constraint	o/e 1.64	unconstrained · MANE · 225 bp · p 1.3e-08 · regional, not allelic
Overall
CADD	11.67	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 0.0387% East Asian · 3/7,754 alleles

Filtering AF 0.0191% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.018%

Overall 0.0197% 154/781,090 alleles · ultra-rare exomes 106/635,366 · genomes 48/145,724 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0387%	2,585
Remaining individualsnot grpmax-eligible	0.0261%	3,831
Finnishnot grpmax-eligible	0.0237%	4,222
European (non-Finnish)	0.0221%	4,523

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.Pro12Arg
Coding: c.35C>G
MANE Select: NM_031215
dbSNP: rs1250790930
Type: single nucleotide variant
Location: chr20:62407242 (GRCh38)
Gene constraint: LOEUF 1 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.39
Residue 12: the 'disordered' region

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

Similar variants

CABLES2 p.Pro12Gln Uncertain significance ★ ⚠ same residue
CABLES2 p.Pro12Leu Uncertain significance ★ ⚠ same residue
CABLES2 p.Pro12Ser Uncertain significance ★ ⚠ same residue
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

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-pro12arg (accessed [today's date]).

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