Is CBLL2 p.Arg95Cys (c.283C>T) pathogenic?

CBLL2 p.Arg95Cys (c.283C>T) is classified Uncertain significance in CBLL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-20). AlphaMissense: likely benign (0.1974); Ultra-rare (popmax 0.0229%, sas).

How common is CBLL2 p.Arg95Cys (c.283C>T) in the general population?

CBLL2 p.Arg95Cys (c.283C>T) is ultra-rare (popmax 0.0229%, sas) (gnomAD).

What do computational predictors say about CBLL2 p.Arg95Cys (c.283C>T)?

AlphaMissense predicts likely benign (score 0.1974) — an in-silico prediction, not a clinical call.

CBLL2 p.Arg95Cys

c.283C>T · VCV4648756

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1974 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0229%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1974	likely benign
REVEL	0.073	moderately benign-leaning
SaProt	LLR -5.12	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 3.8	GERP -0.67, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 1,274 bp · p 0.84 · regional, not allelic
Overall
CADD	16.96	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 0.0229% South Asian · 13/56,778 alleles

Filtering AF 0.0135% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0107%

Overall 0.00182% 22/1,209,813 alleles · ultra-rare exomes 21/1,098,220 · genomes 1/111,593 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0229%	4,368
Middle Eastern	0.0229%	4,376
East Asian	0.00296%	33,773
Remaining individualsnot grpmax-eligible	0.0021%	47,600
European (non-Finnish)	0.00067%	149,209

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: CBLL2
Protein: p.Arg95Cys
Coding: c.283C>T
MANE Select: NM_152577
Type: single nucleotide variant
Location: chrX:22273274 (GRCh38)
Structure: AlphaFold pLDDT 55.14

Full CBLL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CBLL2 p.Arg95His Uncertain significance ★ ⚠ same residue
CBLL2 p.Arg389= Benign ★★ same type
CBLL2 p.Leu215= Benign ★★ same type
CBLL2 p.Ala283Val Uncertain significance ★ ⚠ same type
CBLL2 p.Arg108Gly Uncertain significance ★ ⚠ same type
CBLL2 p.Arg310His Conflicting classifications of pathogenicity ★ ⚠ same type
CBLL2 p.Arg341His Uncertain significance ★ ⚠ same type
CBLL2 p.Arg424Gln 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/cbll2-p-arg95cys (accessed [today's date]).

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