Is CBR1 p.Val138Ile (c.412G>A) pathogenic?

CBR1 p.Val138Ile (c.412G>A) is classified Likely benign in CBR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: likely benign (0.1143); Very rare (popmax 0.00441%, nfe).

How common is CBR1 p.Val138Ile (c.412G>A) in the general population?

CBR1 p.Val138Ile (c.412G>A) is very rare (popmax 0.00441%, nfe) (gnomAD).

What do computational predictors say about CBR1 p.Val138Ile (c.412G>A)?

AlphaMissense predicts likely benign (score 0.1143) — an in-silico prediction, not a clinical call.

CBR1 p.Val138Ile

c.412G>A · VCV4220018

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1143 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00441%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1143	likely benign
REVEL	0.319	indeterminate
SaProt	LLR -9.03	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.8	GERP -0.049
Regional constraint	o/e 0.98	unconstrained · MANE · 2,763 bp · p 0.69 · regional, not allelic
Overall
CADD	17.14	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 0.00441% European (non-Finnish) · 52/1,180,010 alleles

Filtering AF 0.00342% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0031%

Overall 0.00372% 60/1,613,984 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00441%	22,693
South Asian	0.00439%	22,773
Admixed American	0.00333%	30,000
Remaining individualsnot grpmax-eligible	0.0016%	62,482
African / African-American	0.00134%	74,896

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: CBR1
Protein: p.Val138Ile
Coding: c.412G>A
MANE Select: NM_001757
Type: single nucleotide variant
Location: chr21:36072460 (GRCh38)
Gene constraint: LOEUF 1.419 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.88 · 6 PDB
Residue 138: a β-strand

Full CBR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CBR1 p.Thr197= Benign ★★ same type
CBR1 p.Ala209Thr Uncertain significance ★ ⚠ same type
CBR1 p.Ala255Val Uncertain significance ★ ⚠ same type
CBR1 p.Ala52Val Uncertain significance ★ ⚠ same type
CBR1 p.Arg119Gln Uncertain significance ★ ⚠ same type
CBR1 p.Arg159Cys Uncertain significance ★ ⚠ same type
CBR1 p.Arg159His Uncertain significance ★ ⚠ same type
CBR1 p.Arg232Lys 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/cbr1-p-val138ile (accessed [today's date]).

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