Is CBLB p.Arg463Leu (c.1388G>T) pathogenic?

CBLB p.Arg463Leu (c.1388G>T) is classified Uncertain significance in CBLB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-09). AlphaMissense: ambiguous (0.3552); Very rare (popmax 0.005%, amr).

How common is CBLB p.Arg463Leu (c.1388G>T) in the general population?

CBLB p.Arg463Leu (c.1388G>T) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about CBLB p.Arg463Leu (c.1388G>T)?

AlphaMissense predicts ambiguous (score 0.3552) — an in-silico prediction, not a clinical call.

CBLB p.Arg463Leu

c.1388G>T · VCV3485647

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3552 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Computational evidence

Protein change
AlphaMissense	0.3552	ambiguous
REVEL	0.532	indeterminate
SaProt	LLR -5.85	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 164 kb · p 3.4e-12 · regional, not allelic
Overall
CADD	24.6	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 0.005% Admixed American · 3/59,970 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000186% 3/1,613,810 alleles · very rare exomes 3/1,461,586 · genomes 0/152,224 · joint denominator

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: CBLB
Protein: p.Arg463Leu
Coding: c.1388G>T
MANE Select: NM_170662
Type: single nucleotide variant
Location: chr3:105720066 (GRCh38)
Gene constraint: LOEUF 0.406 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 62.88 · 36 PDB

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

Similar variants

CBLB p.Arg670Gln Benign/Likely benign ★★ same type
CBLB p.Pro387= Benign ★★ same type
CBLB p.Pro689= Benign/Likely benign ★★ same type
CBLB p.Ser622Thr Benign/Likely benign ★★ same type
CBLB c.2569+1609A>C Uncertain significance ★ same type
CBLB p.Ala176Pro Uncertain significance ★ ⚠ same type
CBLB p.Ala2Glu Uncertain significance ★ ⚠ same type
CBLB p.Ala592Ser 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/cblb-p-arg463leu (accessed [today's date]).

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