Is CBLL2 p.Arg310His (c.929G>A) pathogenic?

CBLL2 p.Arg310His (c.929G>A) is classified Conflicting classifications of pathogenicity in CBLL2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-02-01). AlphaMissense: likely benign (0.0736); Ultra-rare (popmax 0.0141%, afr).

How common is CBLL2 p.Arg310His (c.929G>A) in the general population?

CBLL2 p.Arg310His (c.929G>A) is ultra-rare (popmax 0.0141%, afr) (gnomAD).

What do computational predictors say about CBLL2 p.Arg310His (c.929G>A)?

AlphaMissense predicts likely benign (score 0.0736) — an in-silico prediction, not a clinical call.

CBLL2 p.Arg310His

c.929G>A · rs746442308 · VCV2660160

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0736 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0141%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0736	likely benign
REVEL	0.016	strongly benign-leaning
SaProt	LLR -5.30	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.9	GERP -3.8
Regional constraint	o/e 1.01	unconstrained · MANE · 1,274 bp · p 0.84 · regional, not allelic
Overall
CADD	0.565	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 0.0141% African / African-American · 8/56,735 alleles

Filtering AF 0.00694% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00506%

Overall 0.00314% 38/1,208,693 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0141%	7,092
Remaining individualsnot grpmax-eligible	0.0105%	9,516
Finnishnot grpmax-eligible	0.00862%	11,604
European (non-Finnish)	0.00235%	42,612

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: CBLL2
Protein: p.Arg310His
Coding: c.929G>A
MANE Select: NM_152577
dbSNP: rs746442308
Type: single nucleotide variant
Location: chrX:22273920 (GRCh38)
Structure: AlphaFold pLDDT 55.14

Full CBLL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CBLL2 p.Arg310Cys Likely benign ★ same residue
CBLL2 p.Arg389= Benign ★★ same type
CBLL2 p.Leu215= Benign ★★ same type
CBLL2 p.Ala283Val Uncertain significance ★ ⚠ same type
CBLL2 p.Arg108Gly Uncertain significance ★ ⚠ same type
CBLL2 p.Arg341His Uncertain significance ★ ⚠ same type
CBLL2 p.Arg424Gln Uncertain significance ★ ⚠ same type
CBLL2 p.Arg95Cys 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/cbll2-p-arg310his (accessed [today's date]).

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