Is CBLL2 p.Pro94Leu (c.281C>T) pathogenic?

CBLL2 p.Pro94Leu (c.281C>T) is classified Uncertain significance in CBLL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-11). AlphaMissense: ambiguous (0.4001); Ultra-rare (popmax 0.037%, sas).

How common is CBLL2 p.Pro94Leu (c.281C>T) in the general population?

CBLL2 p.Pro94Leu (c.281C>T) is ultra-rare (popmax 0.037%, sas) (gnomAD).

What do computational predictors say about CBLL2 p.Pro94Leu (c.281C>T)?

AlphaMissense predicts ambiguous (score 0.4001) — an in-silico prediction, not a clinical call.

CBLL2 p.Pro94Leu

c.281C>T · rs201885236 · VCV2597564

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4001 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.037%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4001	ambiguous
REVEL	0.056	moderately benign-leaning
SaProt	LLR -7.83	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.79	GERP -3.3
Regional constraint	o/e 1.01	unconstrained · MANE · 1,274 bp · p 0.84 · regional, not allelic
Overall
CADD	11.75	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 0.037% South Asian · 21/56,759 alleles

Filtering AF 0.0248% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0208%

Overall 0.00397% 48/1,209,826 alleles · ultra-rare exomes 45/1,098,225 · genomes 3/111,601 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.037%	2,703
Ashkenazi Jewishnot grpmax-eligible	0.0363%	2,753
Middle Eastern	0.023%	4,355
Remaining individualsnot grpmax-eligible	0.0126%	7,936
East Asian	0.00592%	16,879
Admixed American	0.00437%	22,868
European (non-Finnish)	0.000894%	111,905

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.Pro94Leu
Coding: c.281C>T
MANE Select: NM_152577
dbSNP: rs201885236
Type: single nucleotide variant
Location: chrX:22273272 (GRCh38)
Structure: AlphaFold pLDDT 55.14

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

Similar variants

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
CBLL2 p.Arg95Cys 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-pro94leu (accessed [today's date]).

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