Is CBR1 p.Pro258Ser (c.772C>T) pathogenic?

CBR1 p.Pro258Ser (c.772C>T) is classified Uncertain significance in CBR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-25). AlphaMissense: likely benign (0.1671); Very rare (popmax 0.00401%, afr).

How common is CBR1 p.Pro258Ser (c.772C>T) in the general population?

CBR1 p.Pro258Ser (c.772C>T) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about CBR1 p.Pro258Ser (c.772C>T)?

AlphaMissense predicts likely benign (score 0.1671) — an in-silico prediction, not a clinical call.

CBR1 p.Pro258Ser

c.772C>T · VCV4648771

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1671 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1671	likely benign
REVEL	0.22	benign-leaning
SaProt	LLR -11.82	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 0.87, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 2,763 bp · p 0.69 · regional, not allelic
Overall
CADD	24.2	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 0.00401% African / African-American · 3/74,824 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000248% 4/1,613,750 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,941
Remaining individualsnot grpmax-eligible	0.0016%	62,472

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.Pro258Ser
Coding: c.772C>T
MANE Select: NM_001757
Type: single nucleotide variant
Location: chr21:36072820 (GRCh38)
Gene constraint: LOEUF 1.419 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.88 · 6 PDB

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-pro258ser (accessed [today's date]).

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