Is CRBN p.Pro85Arg (c.254C>G) pathogenic?

CRBN p.Pro85Arg (c.254C>G) is classified Uncertain significance in CRBN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-19). AlphaMissense: likely benign (0.236); Very rare (popmax 0.000847%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CRBN p.Pro85Arg (c.254C>G)?

CRBN p.Pro85Arg (c.254C>G) is associated with Inborn genetic diseases (ClinVar).

How common is CRBN p.Pro85Arg (c.254C>G) in the general population?

CRBN p.Pro85Arg (c.254C>G) is very rare (popmax 0.000847%, nfe) (gnomAD).

What do computational predictors say about CRBN p.Pro85Arg (c.254C>G)?

AlphaMissense predicts likely benign (score 0.236) — an in-silico prediction, not a clinical call.

CRBN p.Pro85Arg

c.254C>G · VCV4233963

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.236 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000847%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.236	likely benign
REVEL	0.392	indeterminate
SaProt	LLR -9.60	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 12	GERP 2.4, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 29 kb · p 0.00023 · regional, not allelic
Overall
CADD	25.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000847% European (non-Finnish) · 10/1,180,020 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000684% 10/1,461,872 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: CRBN
Protein: p.Pro85Arg
Coding: c.254C>G
MANE Select: NM_016302
Type: single nucleotide variant
Location: chr3:3174182 (GRCh38)
Gene constraint: LOEUF 1.147 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.87 · 104 PDB
Residue 85: the lon n-terminal domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CRBN p.Pro85= Likely benign ★ same residue
CRBN p.Arg373Trp Uncertain significance ★★ ⚠ same condition
CRBN p.Gln7Arg Uncertain significance ★★ ⚠ same condition
CRBN p.Pro212Ala Uncertain significance ★★ ⚠ same condition
CRBN p.Thr418= Likely benign ★★ same condition
CRBN p.Ala10Pro Uncertain significance ★ ⚠ same condition
CRBN p.Ala10Ser Uncertain significance ★ ⚠ same condition
CRBN p.Ala10Val Uncertain significance ★ ⚠ same condition

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/crbn-p-pro85arg (accessed [today's date]).

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