Is CBLB p.Ser622Thr (c.1865G>C) pathogenic?

CBLB p.Ser622Thr (c.1865G>C) is classified Benign/Likely benign in CBLB (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-11-01). AlphaMissense: likely benign (0.0619); Low-frequency (popmax 1.01%, mid).

How common is CBLB p.Ser622Thr (c.1865G>C) in the general population?

CBLB p.Ser622Thr (c.1865G>C) is low-frequency (popmax 1.01%, mid) (gnomAD).

What do computational predictors say about CBLB p.Ser622Thr (c.1865G>C)?

AlphaMissense predicts likely benign (score 0.0619) — an in-silico prediction, not a clinical call.

CBLB p.Ser622Thr

c.1865G>C · rs41302192 · VCV133823

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0619 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.01%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0619	likely benign
REVEL	0.177	moderately benign-leaning
SaProt	LLR -6.88	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 2.7	GERP -0.088, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 45 kb · p 0.35 · regional, not allelic
Overall
CADD	13.67	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 1.01% Middle Eastern · 61/6,062 alleles

Filtering AF 0.804% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.731%

Overall 0.653% 10,535/1,614,136 alleles · low-frequency

Ancestry group	Frequency	1 in
Middle Easterngrpmax	1.01%	99
Finnishnot grpmax-eligible	0.868%	115
Ashkenazi Jewishnot grpmax-eligible	0.811%	123
European (non-Finnish)	0.73%	137
Remaining individualsnot grpmax-eligible	0.638%	157
South Asian	0.527%	190
Admixed American	0.17%	589
African / African-American	0.112%	893

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.Ser622Thr
Coding: c.1865G>C
MANE Select: NM_170662
dbSNP: rs41302192
Type: single nucleotide variant
Location: chr3:105702188 (GRCh38)
Gene constraint: LOEUF 0.406 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 62.88 · 36 PDB
Residue 622: 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 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
CBLB p.Ala928Val 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-ser622thr (accessed [today's date]).

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