Is CABLES2 p.Arg404Cys (c.1210C>T) pathogenic?

CABLES2 p.Arg404Cys (c.1210C>T) is classified Uncertain significance in CABLES2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-07). AlphaMissense: likely pathogenic (0.9918); Ultra-rare (popmax 0.0111%, nfe).

How common is CABLES2 p.Arg404Cys (c.1210C>T) in the general population?

CABLES2 p.Arg404Cys (c.1210C>T) is ultra-rare (popmax 0.0111%, nfe) (gnomAD).

What do computational predictors say about CABLES2 p.Arg404Cys (c.1210C>T)?

AlphaMissense predicts likely pathogenic (score 0.9918) — an in-silico prediction, not a clinical call.

CABLES2 p.Arg404Cys

c.1210C>T · VCV3994313

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9918 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9918	likely pathogenic · top 10% in CABLES2
REVEL	0.319	indeterminate
SaProt	LLR -13.98	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 16 kb · p 1.5e-05 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0111% European (non-Finnish) · 131/1,180,036 alleles

Filtering AF 0.00952% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00896%

Overall 0.00849% 137/1,613,234 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0111%	9,008
African / African-American	0.004%	24,984
Remaining individualsnot grpmax-eligible	0.0032%	31,240
East Asian	0.00223%	44,886

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.Arg404Cys
Coding: c.1210C>T
MANE Select: NM_031215
Type: single nucleotide variant
Location: chr20:62391335 (GRCh38)
Gene constraint: LOEUF 1 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.39

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-arg404cys (accessed [today's date]).

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