Is CBL p.Gln175His (c.525G>T) pathogenic?

CBL p.Gln175His (c.525G>T) is classified Uncertain significance in CBL (ClinVar, Single submitter, 1 submitter; last evaluated 2017-03-16). AlphaMissense: ambiguous (0.5625); Very rare (popmax 0.0022%, sas).

How common is CBL p.Gln175His (c.525G>T) in the general population?

CBL p.Gln175His (c.525G>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about CBL p.Gln175His (c.525G>T)?

AlphaMissense predicts ambiguous (score 0.5625) — an in-silico prediction, not a clinical call.

CBL p.Gln175His

c.525G>T · rs754381153 · VCV424312

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5625 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Computational evidence

Protein change
AlphaMissense	0.5625	ambiguous
REVEL	0.554	indeterminate
SaProt	LLR -8.89	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP -0.37, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 45 kb · p 4.6e-13 · regional, not allelic
Overall
CADD	22.6	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 0.0022% South Asian · 2/91,076 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000137% 2/1,461,726 alleles · very rare

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: CBL
Protein: p.Gln175His
Coding: c.525G>T
MANE Select: NM_005188
dbSNP: rs754381153
Type: single nucleotide variant
Location: chr11:119271816 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 175: the cbl-ptb domain; the 'sufficient for interaction with ephb1' region; the '4h' region

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

Similar variants

CBL p.Gln175Glu Uncertain significance ★★ ⚠ same residue
CBL p.Gln175Arg Uncertain significance ★ ⚠ same residue
CBL p.Gln175= Likely benign ★ same residue
CBL c.1096-1G>C Pathogenic/Likely pathogenic ★★ same type
CBL c.1096-1G>T Pathogenic ★★ same type
CBL c.1096-2A>T Pathogenic ★★ same type
CBL c.1228-2A>G Pathogenic/Likely pathogenic ★★ same type
CBL p.Arg420Gln Pathogenic/Likely pathogenic ★★ 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/cbl-p-gln175his (accessed [today's date]).

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