Is BICD2 p.Arg23Pro (c.68G>C) pathogenic?

BICD2 p.Arg23Pro (c.68G>C) is classified Uncertain significance in BICD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-12). AlphaMissense: likely pathogenic (0.836); Very rare (popmax 8.53e-05%, nfe); Associated with BICD2-related disorder.

What condition is associated with BICD2 p.Arg23Pro (c.68G>C)?

BICD2 p.Arg23Pro (c.68G>C) is associated with BICD2-related disorder (ClinVar).

How common is BICD2 p.Arg23Pro (c.68G>C) in the general population?

BICD2 p.Arg23Pro (c.68G>C) is very rare (popmax 8.53e-05%, nfe) (gnomAD).

What do computational predictors say about BICD2 p.Arg23Pro (c.68G>C)?

AlphaMissense predicts likely pathogenic (score 0.836) — an in-silico prediction, not a clinical call.

BICD2 p.Arg23Pro

c.68G>C · rs2537622342 · VCV2631939

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.836 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.53e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

BICD2-related disorder

Computational evidence

Protein change
AlphaMissense	0.836	likely pathogenic
REVEL	0.274	benign-leaning
SaProt	LLR -9.10	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	GERP 1.4, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 42 kb · p 0.00095 · regional, not allelic
Overall
CADD	33.0	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 8.53e-05% European (non-Finnish) · 1/1,172,034 alleles

Overall 6.96e-05% 1/1,437,280 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: BICD2
Protein: p.Arg23Pro
Coding: c.68G>C
MANE Select: NM_001003800
dbSNP: rs2537622342
Type: single nucleotide variant
Location: chr9:92764677 (GRCh38)
Gene constraint: LOEUF 0.507 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 78.89 · 2 PDB
Residue 23: an α-helix

Full BICD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

BICD2-related disorder

Similar variants

BICD2 p.Arg23= Likely benign ★ same residue
BICD2 p.Arg160His Uncertain significance ★★ ⚠ same condition
BICD2 p.Tyr114Ter Pathogenic ★ same condition
BICD2 p.Arg12Gln Uncertain significance ★ ⚠ same condition
BICD2 p.Arg566Cys Conflicting classifications of pathogenicity ★ ⚠ same condition
BICD2 p.His540Arg Uncertain significance ★ ⚠ same condition
BICD2 p.His89Arg Uncertain significance ★ ⚠ same condition
BICD2 p.Ala791Gly 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/bicd2-p-arg23pro (accessed [today's date]).

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