Is CBLB p.Arg510Cys (c.1528C>T) pathogenic?

CBLB p.Arg510Cys (c.1528C>T) is classified Uncertain significance in CBLB (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-03). AlphaMissense: likely pathogenic (0.9904); Very rare (popmax 0.00333%, amr).

How common is CBLB p.Arg510Cys (c.1528C>T) in the general population?

CBLB p.Arg510Cys (c.1528C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about CBLB p.Arg510Cys (c.1528C>T)?

AlphaMissense predicts likely pathogenic (score 0.9904) — an in-silico prediction, not a clinical call.

CBLB p.Arg510Cys

c.1528C>T · VCV3996100

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9904 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9904	likely pathogenic
REVEL	0.673	pathogenic-leaning
SaProt	LLR -9.96	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 2, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 164 kb · p 3.4e-12 · regional, not allelic
Overall
CADD	33.0	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 0.00333% Admixed American · 2/60,030 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000867% 14/1,614,162 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,015
South Asian	0.0022%	45,539
European (non-Finnish)	0.000847%	118,001

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.Arg510Cys
Coding: c.1528C>T
MANE Select: NM_170662
Type: single nucleotide variant
Location: chr3:105704053 (GRCh38)
Gene constraint: LOEUF 0.406 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 62.88 · 36 PDB
Residue 510: a UniProt-annotated variant site (in admio3; likely pathogenic); the 'disordered' region

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

Similar variants

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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-arg510cys (accessed [today's date]).

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