Is CBR4 p.Leu46Val (c.136C>G) pathogenic?

CBR4 p.Leu46Val (c.136C>G) is classified Uncertain significance in CBR4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-07). AlphaMissense: likely benign (0.1692); Ultra-rare (popmax 0.0188%, nfe).

How common is CBR4 p.Leu46Val (c.136C>G) in the general population?

CBR4 p.Leu46Val (c.136C>G) is ultra-rare (popmax 0.0188%, nfe) (gnomAD).

What do computational predictors say about CBR4 p.Leu46Val (c.136C>G)?

AlphaMissense predicts likely benign (score 0.1692) — an in-silico prediction, not a clinical call.

CBR4 p.Leu46Val

c.136C>G · rs568502080 · VCV3138039

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1692 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0188%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1692	likely benign
REVEL	0.359	indeterminate
SaProt	LLR -11.39	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.2	GERP 2.3, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 20 kb · p 0.35 · regional, not allelic
Overall
CADD	22.8	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 0.0188% European (non-Finnish) · 222/1,179,140 alleles

Filtering AF 0.0167% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.016%

Overall 0.0143% 230/1,611,520 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0188%	5,311
Remaining individualsnot grpmax-eligible	0.00962%	10,393
African / African-American	0.00267%	37,502

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.Leu46Val
Coding: c.136C>G
MANE Select: NM_032783
dbSNP: rs568502080
Type: single nucleotide variant
Location: chr4:169009954 (GRCh38)
Gene constraint: LOEUF 1.791 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.69 · 2 PDB

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-leu46val (accessed [today's date]).

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