Is CBLB p.Ala621= (c.1863G>A) pathogenic?

CBLB p.Ala621= (c.1863G>A) is classified Benign in CBLB (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-05-28). Common (popmax 13.3%, eas) — too common for a highly-penetrant pathogenic allele; Associated with CBLB-related disorder.

What condition is associated with CBLB p.Ala621= (c.1863G>A)?

CBLB p.Ala621= (c.1863G>A) is associated with CBLB-related disorder (ClinVar).

CBLB p.Ala621=

Q: How common is CBLB p.Ala621= (c.1863G>A) in the general population?

CBLB p.Ala621= (c.1863G>A) is common (popmax 13.3%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1863G>A · rs3772534 · VCV3060876

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 13.3%, eas) — too common for a highly-penetrant pathogenic allele

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 -7	GERP -3.4
Overall
CADD	0.218	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 13.3% East Asian · 5,978/44,872 alleles

Filtering AF 13% ClinGen BA1/BS1 input FAF95, joint · FAF99 12.9%

Overall 2.92% 47,088/1,614,090 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	13.3%	8
Amishnot grpmax-eligible	8.02%	12
South Asian	6.73%	15
Remaining individualsnot grpmax-eligible	3.3%	30
Middle Eastern	3.04%	33
European (non-Finnish)	2.6%	38
Ashkenazi Jewishnot grpmax-eligible	1.78%	56
Admixed American	1.24%	81
Finnishnot grpmax-eligible	0.576%	173
African / African-American	0.432%	232

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.Ala621=
Coding: c.1863G>A
MANE Select: NM_170662
dbSNP: rs3772534
Type: single nucleotide variant
Location: chr3:105702190 (GRCh38)
Gene constraint: LOEUF 0.406 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 62.88 · 36 PDB
Residue 621: a UniProt-annotated variant site (in admio3; likely pathogenic)

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

Disease context

CBLB-related disorder

Similar variants

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
CBLB p.Pro280= 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-ala621 (accessed [today's date]).

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