Is CBR4 p.Arg34Lys (c.101G>A) pathogenic?

CBR4 p.Arg34Lys (c.101G>A) is classified Uncertain significance in CBR4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-02). AlphaMissense: likely pathogenic (0.5748); Very rare (popmax 8.48e-05%, nfe).

How common is CBR4 p.Arg34Lys (c.101G>A) in the general population?

CBR4 p.Arg34Lys (c.101G>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CBR4 p.Arg34Lys (c.101G>A)?

AlphaMissense predicts likely pathogenic (score 0.5748) — an in-silico prediction, not a clinical call.

CBR4 p.Arg34Lys

c.101G>A · VCV3996155

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5748 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5748	likely pathogenic
REVEL	0.737	pathogenic-leaning
SaProt	LLR -11.04	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 7.4	GERP 2.3, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 20 kb · p 0.35 · regional, not allelic
Overall
CADD	25.5	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 8.48e-05% European (non-Finnish) · 1/1,179,798 alleles

Overall 6.84e-05% 1/1,461,158 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: CBR4
Protein: p.Arg34Lys
Coding: c.101G>A
MANE Select: NM_032783
Type: single nucleotide variant
Location: chr4:169009989 (GRCh38)
Gene constraint: LOEUF 1.791 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.69 · 2 PDB
Residue 34: a β-strand; a binding site

Full CBR4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PALLD c.2199+4C>T Uncertain significance ★★ same type
PALLD c.*110G>C Uncertain significance ★★ same type
PALLD c.*127C>G Uncertain significance ★★ same type
PALLD c.*135C>T Uncertain significance ★★ same type
PALLD c.*155C>G Uncertain significance ★★ same type
PALLD c.*161C>T Uncertain significance ★★ same type
PALLD c.*182T>A Uncertain significance ★★ same type
PALLD c.*194G>C 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/cbr4-p-arg34lys (accessed [today's date]).

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