Is CBR4 p.Val57Phe (c.169G>T) pathogenic?

CBR4 p.Val57Phe (c.169G>T) is classified Uncertain significance in CBR4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-05). AlphaMissense: likely pathogenic (0.7873); Very rare (popmax 0.0089%, nfe).

How common is CBR4 p.Val57Phe (c.169G>T) in the general population?

CBR4 p.Val57Phe (c.169G>T) is very rare (popmax 0.0089%, nfe) (gnomAD).

What do computational predictors say about CBR4 p.Val57Phe (c.169G>T)?

AlphaMissense predicts likely pathogenic (score 0.7873) — an in-silico prediction, not a clinical call.

CBR4 p.Val57Phe

c.169G>T · VCV4648783

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7873 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0089%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7873	likely pathogenic
REVEL	0.838	moderately pathogenic-leaning
SaProt	LLR -14.75	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.9	GERP 2.1, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 20 kb · p 0.35 · regional, not allelic
Overall
CADD	24.9	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 0.0089% European (non-Finnish) · 104/1,169,062 alleles

Filtering AF 0.00748% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00699%

Overall 0.00681% 108/1,586,418 alleles · very rare exomes 103/1,434,248 · genomes 5/152,170 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0089%	11,241
Admixed American	0.00365%	27,429
Remaining individualsnot grpmax-eligible	0.00326%	30,656

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.Val57Phe
Coding: c.169G>T
MANE Select: NM_032783
Type: single nucleotide variant
Location: chr4:169007730 (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-val57phe (accessed [today's date]).

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