Is CBLB p.Arg596Trp (c.1786C>T) pathogenic?

CBLB p.Arg596Trp (c.1786C>T) is classified Uncertain significance in CBLB (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-03). AlphaMissense: likely benign (0.297); Very rare (popmax 0.00267%, afr).

How common is CBLB p.Arg596Trp (c.1786C>T) in the general population?

CBLB p.Arg596Trp (c.1786C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about CBLB p.Arg596Trp (c.1786C>T)?

AlphaMissense predicts likely benign (score 0.297) — an in-silico prediction, not a clinical call.

CBLB p.Arg596Trp

c.1786C>T · rs759775874 · VCV3137966

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.297 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.297	likely benign
REVEL	0.634	indeterminate
SaProt	LLR -8.64	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP 1.1, phastCons 0.6
Regional constraint	o/e 1.04	unconstrained · MANE · 45 kb · p 0.35 · regional, not allelic
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,844 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.00062% 10/1,613,810 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,243
African / African-Americangrpmax	0.00267%	37,422
East Asian	0.00223%	44,880
Admixed American	0.00167%	59,984
European (non-Finnish)	0.000339%	294,989

Remaining individuals 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.Arg596Trp
Coding: c.1786C>T
MANE Select: NM_170662
dbSNP: rs759775874
Type: single nucleotide variant
Location: chr3:105702267 (GRCh38)
Gene constraint: LOEUF 0.406 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 62.88 · 36 PDB
Residue 596: a UniProt-annotated variant site (in admio3; likely pathogenic)

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

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CBLB p.Ser622Thr Benign/Likely benign ★★ same type
CBLB c.2569+1609A>C Uncertain significance ★ same type
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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-arg596trp (accessed [today's date]).

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