Is CBLL2 p.Ser115Cys (c.343A>T) pathogenic?

CBLL2 p.Ser115Cys (c.343A>T) is classified Uncertain significance in CBLL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-26). AlphaMissense: likely benign (0.2099); Ultra-rare (popmax 0.0207%, eas).

How common is CBLL2 p.Ser115Cys (c.343A>T) in the general population?

CBLL2 p.Ser115Cys (c.343A>T) is ultra-rare (popmax 0.0207%, eas) (gnomAD).

What do computational predictors say about CBLL2 p.Ser115Cys (c.343A>T)?

AlphaMissense predicts likely benign (score 0.2099) — an in-silico prediction, not a clinical call.

CBLL2 p.Ser115Cys

c.343A>T · VCV3263644

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2099 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0207%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2099	likely benign
REVEL	0.183	benign-leaning
SaProt	LLR -7.99	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 1	GERP -5.1
Regional constraint	o/e 1.01	unconstrained · MANE · 1,274 bp · p 0.84 · regional, not allelic
Overall
CADD	15.81	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 0.0207% East Asian · 7/33,793 alleles

Filtering AF 0.00967% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0068%

Overall 0.000578% 7/1,210,236 alleles · ultra-rare

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.Ser115Cys
Coding: c.343A>T
MANE Select: NM_152577
Type: single nucleotide variant
Location: chrX:22273334 (GRCh38)
Structure: AlphaFold pLDDT 55.14
Residue 115: the 'hyb domain' 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-ser115cys (accessed [today's date]).

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