Is CBLB p.Pro910Leu (c.2729C>T) pathogenic?

CBLB p.Pro910Leu (c.2729C>T) is classified Uncertain significance in CBLB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-24). AlphaMissense: likely pathogenic (0.564); Ultra-rare (popmax 0.0285%, sas).

How common is CBLB p.Pro910Leu (c.2729C>T) in the general population?

CBLB p.Pro910Leu (c.2729C>T) is ultra-rare (popmax 0.0285%, sas) (gnomAD).

What do computational predictors say about CBLB p.Pro910Leu (c.2729C>T)?

AlphaMissense predicts likely pathogenic (score 0.564) — an in-silico prediction, not a clinical call.

CBLB p.Pro910Leu

c.2729C>T · VCV4219946

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.564 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0285%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.564	likely pathogenic
REVEL	0.633	indeterminate
SaProt	LLR -8.66	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 45 kb · p 0.35 · regional, not allelic
Overall
CADD	31.0	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 0.0285% South Asian · 26/91,070 alleles

Filtering AF 0.0199% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0171%

Overall 0.00378% 61/1,613,928 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0285%	3,503
East Asian	0.0223%	4,487
African / African-American	0.0133%	7,500
Finnishnot grpmax-eligible	0.0109%	9,147
Remaining individualsnot grpmax-eligible	0.0048%	20,831
European (non-Finnish)	0.000424%	235,980

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.Pro910Leu
Coding: c.2729C>T
MANE Select: NM_170662
Type: single nucleotide variant
Location: chr3:105659190 (GRCh38)
Gene constraint: LOEUF 0.406 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 62.88 · 36 PDB
Residue 910: an α-helix; the 'disordered' region; the 'interaction with sh3kbp1' region; a UniProt-annotated variant site (in admio3; likely pathogenic)

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-pro910leu (accessed [today's date]).

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