Is CBLB p.Asp188His (c.562G>C) pathogenic?

CBLB p.Asp188His (c.562G>C) is classified Uncertain significance in CBLB (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-19). AlphaMissense: ambiguous (0.4325); Very rare (popmax 6.84e-05%).

How common is CBLB p.Asp188His (c.562G>C) in the general population?

CBLB p.Asp188His (c.562G>C) is very rare (popmax 6.84e-05%) (gnomAD).

What do computational predictors say about CBLB p.Asp188His (c.562G>C)?

AlphaMissense predicts ambiguous (score 0.4325) — an in-silico prediction, not a clinical call.

CBLB p.Asp188His

c.562G>C · rs2547247537 · VCV2336363

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4325 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Computational evidence

Protein change
AlphaMissense	0.4325	ambiguous
REVEL	0.583	indeterminate
SaProt	LLR -11.04	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.8, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 164 kb · p 3.4e-12 · regional, not allelic
Overall
CADD	28.2	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 6.84e-05%

Overall 6.84e-05% 1/1,461,088 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: CBLB
Protein: p.Asp188His
Coding: c.562G>C
MANE Select: NM_170662
dbSNP: rs2547247537
Type: single nucleotide variant
Location: chr3:105776400 (GRCh38)
Gene constraint: LOEUF 0.406 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 62.88 · 36 PDB
Residue 188: the cbl-ptb domain; the 'ef-hand-like' region

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 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-asp188his (accessed [today's date]).

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