Is CBLB p.Pro280= (c.840C>T) pathogenic?

CBLB p.Pro280= (c.840C>T) is classified Benign in CBLB (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-03-01). Low-frequency (popmax 2.53%, mid); Associated with CBLB-related disorder.

What condition is associated with CBLB p.Pro280= (c.840C>T)?

CBLB p.Pro280= (c.840C>T) is associated with CBLB-related disorder (ClinVar).

How common is CBLB p.Pro280= (c.840C>T) in the general population?

CBLB p.Pro280= (c.840C>T) is low-frequency (popmax 2.53%, mid) (gnomAD).

CBLB p.Pro280=

c.840C>T · rs9657906 · VCV3059767

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

low-frequency (popmax 2.53%, mid)

Conditions

CBLB-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.5	GERP -4.3
Overall
CADD	3.422	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.53% Middle Eastern · 153/6,054 alleles

Filtering AF 2.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.08%

Overall 1.81% 29,078/1,610,656 alleles · low-frequency exomes 26,825/1,458,498 · genomes 2,253/152,158 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	3.69%	27
Middle Easterngrpmax	2.53%	40
European (non-Finnish)	2.04%	49
Remaining individualsnot grpmax-eligible	1.84%	54
Admixed American	1.5%	67
Finnishnot grpmax-eligible	1.48%	68
South Asian	0.627%	160
African / African-American	0.364%	274
Amishnot grpmax-eligible	0.11%	912
East Asian	0.00446%	22,407

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro280=
Coding: c.840C>T
MANE Select: NM_170662
dbSNP: rs9657906
Type: single nucleotide variant
Location: chr3:105745922 (GRCh38)
Gene constraint: LOEUF 0.406 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 62.88 · 36 PDB
Residue 280: the cbl-ptb domain; the 'sh2-like' region

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

Disease context

CBLB-related disorder

Similar variants

CBLB p.Ala621= Benign same condition
CBLB p.Arg570= Likely benign same condition
CBLB p.Asn466Asp Benign same condition
CBLB p.Asn883Asp Benign same condition
CBLB p.Asp351= Benign same condition
CBLB p.Asp424= Benign same condition
CBLB p.Leu447= Benign same condition
CBLB p.Lys275= Benign same condition

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-pro280 (accessed [today's date]).

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