Is CBL p.Leu62His (c.185T>A) pathogenic?

CBL p.Leu62His (c.185T>A) is classified Uncertain significance in CBL (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-17). AlphaMissense: likely pathogenic (0.9023); Very rare (popmax 0.00138%, afr); Associated with Cardiovascular phenotype.

What condition is associated with CBL p.Leu62His (c.185T>A)?

CBL p.Leu62His (c.185T>A) is associated with Cardiovascular phenotype, RASopathy (ClinVar).

How common is CBL p.Leu62His (c.185T>A) in the general population?

CBL p.Leu62His (c.185T>A) is very rare (popmax 0.00138%, afr) (gnomAD).

What do computational predictors say about CBL p.Leu62His (c.185T>A)?

AlphaMissense predicts likely pathogenic (score 0.9023) — an in-silico prediction, not a clinical call.

CBL p.Leu62His

c.185T>A · rs1182439351 · VCV2144546

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9023 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00138%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9023	likely pathogenic
REVEL	0.724	pathogenic-leaning
SaProt	LLR -8.75	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 7.2	GERP 1.4, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 26 kb · p 0.76 · regional, not allelic
Overall
CADD	27.9	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 0.00138% African / African-American · 1/72,562 alleles

Filtering AF 0.000254% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000163%

Overall 0.000517% 8/1,547,568 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00138%	72,562
European (non-Finnish)	0.000611%	163,705

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.Leu62His
Coding: c.185T>A
MANE Select: NM_005188
dbSNP: rs1182439351
Type: single nucleotide variant
Location: chr11:119206602 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 62: the cbl-ptb domain; the 'sufficient for interaction with ephb1' region; the '4h' region; an α-helix

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.Leu62Val Uncertain significance ★★ ⚠ same residue
CBL p.Leu62Phe Uncertain significance ★ ⚠ same residue
CBL p.Leu62= Likely benign ★ 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

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-leu62his (accessed [today's date]).

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