Is CBL p.His398Pro (c.1193A>C) pathogenic?

CBL p.His398Pro (c.1193A>C) is classified Uncertain significance in CBL (ClinVar, Single submitter, 2 submitters; last evaluated 2018-01-13). AlphaMissense: likely pathogenic (0.9995); Very rare (popmax 0.00017%, nfe); Associated with CBL-related disorder.

What condition is associated with CBL p.His398Pro (c.1193A>C)?

CBL p.His398Pro (c.1193A>C) is associated with CBL-related disorder (ClinVar).

How common is CBL p.His398Pro (c.1193A>C) in the general population?

CBL p.His398Pro (c.1193A>C) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about CBL p.His398Pro (c.1193A>C)?

AlphaMissense predicts likely pathogenic (score 0.9995) — an in-silico prediction, not a clinical call.

CBL p.His398Pro

c.1193A>C · rs1303812580 · VCV880137

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9995 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CBL-related disorder

Computational evidence

Protein change
AlphaMissense	0.9995	likely pathogenic · top 8% in CBL
REVEL	0.949	strongly pathogenic-leaning
SaProt	LLR -14.50	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 2.1, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 22 kb · p 0.19 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00017% European (non-Finnish) · 2/1,179,850 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,834 alleles · very rare exomes 2/1,461,692 · genomes 1/152,142 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
European (non-Finnish)grpmax	0.00017%	589,925

Ashkenazi Jewish 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: CBL
Protein: p.His398Pro
Coding: c.1193A>C
MANE Select: NM_005188
dbSNP: rs1303812580
Type: single nucleotide variant
Location: chr11:119278263 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 398: the 'required for ubiquitination of spred2' region; a β-strand

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

Disease context

CBL-related disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CBL p.His398Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
CBL p.His398Asn Likely pathogenic ★ same residue
CBL p.His398Tyr Conflicting classifications of pathogenicity ★ ⚠ same residue
CBL p.His398= Likely benign ★ same residue
CBL c.1096-1G>C Pathogenic/Likely pathogenic ★★ same condition
CBL c.1096-1G>T Pathogenic ★★ same condition
CBL c.1096-2A>T Pathogenic ★★ same condition
CBL c.1228-2A>G Pathogenic/Likely pathogenic ★★ same condition

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-his398pro (accessed [today's date]).

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