Is CBL p.Arg116Met (c.347G>T) pathogenic?

CBL p.Arg116Met (c.347G>T) is classified Uncertain significance in CBL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2020-05-18). AlphaMissense: likely pathogenic (0.9015); Very rare (popmax 0.000169%, nfe).

How common is CBL p.Arg116Met (c.347G>T) in the general population?

CBL p.Arg116Met (c.347G>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about CBL p.Arg116Met (c.347G>T)?

AlphaMissense predicts likely pathogenic (score 0.9015) — an in-silico prediction, not a clinical call.

CBL p.Arg116Met

c.347G>T · rs748412298 · VCV932225

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9015 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9015	likely pathogenic
REVEL	0.538	indeterminate
SaProt	LLR -11.70	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.43 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 45 kb · p 4.6e-13 · regional, not allelic
Overall
CADD	28.5	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 0.000169% European (non-Finnish) · 2/1,179,962 alleles

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

Overall 0.000137% 2/1,461,764 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.Arg116Met
Coding: c.347G>T
MANE Select: NM_005188
dbSNP: rs748412298
Type: single nucleotide variant
Location: chr11:119232599 (GRCh38)
Gene constraint: LOEUF 0.622 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 64.27 · 34 PDB
Residue 116: 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

Similar variants

CBL p.Arg116Gly Uncertain significance ★★ ⚠ same residue
CBL p.Arg116= 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
CBL p.Arg420Leu 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-arg116met (accessed [today's date]).

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