Is CBLL2 p.Ile276Met (c.828A>G) pathogenic?

CBLL2 p.Ile276Met (c.828A>G) is classified Likely benign in CBLL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-23). AlphaMissense: likely benign (0.0675); Ultra-rare (popmax 0.0685%, mid).

How common is CBLL2 p.Ile276Met (c.828A>G) in the general population?

CBLL2 p.Ile276Met (c.828A>G) is ultra-rare (popmax 0.0685%, mid) (gnomAD).

What do computational predictors say about CBLL2 p.Ile276Met (c.828A>G)?

AlphaMissense predicts likely benign (score 0.0675) — an in-silico prediction, not a clinical call.

CBLL2 p.Ile276Met

c.828A>G · rs750306802 · VCV2464576

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0675 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0685%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0675	likely benign
REVEL	0.062	moderately benign-leaning
SaProt	LLR -6.83	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 -0.061	GERP -3.1
Regional constraint	o/e 1.01	unconstrained · MANE · 1,274 bp · p 0.84 · regional, not allelic
Overall
CADD	0.311	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 0.0685% Middle Eastern · 3/4,377 alleles

Filtering AF 0.0186% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00991%

Overall 0.0038% 46/1,208,967 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0685%	1,459
Admixed American	0.00658%	15,193
European (non-Finnish)	0.00425%	23,553
Remaining individualsnot grpmax-eligible	0.0021%	47,581
South Asian	0.00176%	56,710

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.Ile276Met
Coding: c.828A>G
MANE Select: NM_152577
dbSNP: rs750306802
Type: single nucleotide variant
Location: chrX:22273819 (GRCh38)
Structure: AlphaFold pLDDT 55.14
Residue 276: the 'disordered' region

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-ile276met (accessed [today's date]).

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