Is CABLES2 p.Pro74Leu (c.221C>T) pathogenic?

CABLES2 p.Pro74Leu (c.221C>T) is classified Uncertain significance in CABLES2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-19). AlphaMissense: likely benign (0.0894); Rare (popmax 0.116%, afr).

How common is CABLES2 p.Pro74Leu (c.221C>T) in the general population?

CABLES2 p.Pro74Leu (c.221C>T) is rare (popmax 0.116%, afr) (gnomAD).

What do computational predictors say about CABLES2 p.Pro74Leu (c.221C>T)?

AlphaMissense predicts likely benign (score 0.0894) — an in-silico prediction, not a clinical call.

CABLES2 p.Pro74Leu

c.221C>T · VCV3262647

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0894 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.116%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0894	likely benign
REVEL	0.049	moderately benign-leaning
SaProt	LLR -8.77	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 3	GERP -0.78, phastCons 1
Regional constraint	o/e 1.64	unconstrained · MANE · 225 bp · p 1.3e-08 · regional, not allelic
Overall
CADD	20.8	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 0.116% African / African-American · 69/59,494 alleles

Filtering AF 0.094% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0859%

Overall 0.00736% 80/1,087,668 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.116%	862
Remaining individualsnot grpmax-eligible	0.0251%	3,985
Admixed American	0.0104%	9,583

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.Pro74Leu
Coding: c.221C>T
MANE Select: NM_031215
Type: single nucleotide variant
Location: chr20:62407056 (GRCh38)
Gene constraint: LOEUF 1 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.39
Residue 74: 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-pro74leu (accessed [today's date]).

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