Is CBL p.Ile199Val (c.595A>G) pathogenic?

CBL p.Ile199Val (c.595A>G) is classified Conflicting classifications of pathogenicity in CBL (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-12-09). AlphaMissense: likely benign (0.0792); Very rare (popmax 0.00167%, amr); Associated with Cardiovascular phenotype.

What condition is associated with CBL p.Ile199Val (c.595A>G)?

CBL p.Ile199Val (c.595A>G) is associated with Cardiovascular phenotype, RASopathy (ClinVar).

How common is CBL p.Ile199Val (c.595A>G) in the general population?

CBL p.Ile199Val (c.595A>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CBL p.Ile199Val (c.595A>G)?

AlphaMissense predicts likely benign (score 0.0792) — an in-silico prediction, not a clinical call.

CBL p.Ile199Val

c.595A>G · rs397517082 · VCV45210

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0792 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0792	likely benign
REVEL	0.446	indeterminate
SaProt	LLR -9.74	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.88	acceptor gain · deltas
Pangolin	Δ0.25	gain · loss 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 45 kb · p 4.6e-13 · regional, not allelic
Overall
CADD	34.0	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 0.00167% Admixed American · 1/60,002 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.00155% 25/1,613,772 alleles · very rare exomes 24/1,461,574 · genomes 1/152,198 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0439%	2,277
Remaining individualsnot grpmax-eligible	0.0032%	31,242
Admixed Americangrpmax	0.00167%	60,002
South Asian	0.0011%	91,078
European (non-Finnish)	0.000678%	147,473

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.Ile199Val
Coding: c.595A>G
MANE Select: NM_005188
dbSNP: rs397517082
Type: single nucleotide variant
Location: chr11:119273872 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 199: the cbl-ptb domain; the 'sufficient for interaction with ephb1' region; the 'ef-hand-like' region; a β-strand

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: RASopathy

Similar variants

CBL p.Ile199Met Uncertain significance ★★ ⚠ same residue
CBL p.Ile199Thr Uncertain significance ★ ⚠ same residue
CBL c.1096-1G>C Pathogenic/Likely pathogenic ★★ same condition
CBL c.1096-1G>T Pathogenic ★★ same condition
CBL c.1228-2A>G Pathogenic/Likely pathogenic ★★ same condition
CBL p.Arg420Gln Pathogenic/Likely pathogenic ★★ same condition
CBL p.Arg420Leu Likely pathogenic ★★ same condition
CBL p.Gln367Arg 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-ile199val (accessed [today's date]).

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