Is BICD2 p.Arg581His (c.1742G>A) pathogenic?

BICD2 p.Arg581His (c.1742G>A) is classified Conflicting classifications of pathogenicity in BICD2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-08-19). AlphaMissense: likely benign (0.1263); Ultra-rare (popmax 0.0125%, nfe); Associated with Inborn genetic diseases.

What condition is associated with BICD2 p.Arg581His (c.1742G>A)?

BICD2 p.Arg581His (c.1742G>A) is associated with Inborn genetic diseases, autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures (ClinVar).

How common is BICD2 p.Arg581His (c.1742G>A) in the general population?

BICD2 p.Arg581His (c.1742G>A) is ultra-rare (popmax 0.0125%, nfe) (gnomAD).

What do computational predictors say about BICD2 p.Arg581His (c.1742G>A)?

AlphaMissense predicts likely benign (score 0.1263) — an in-silico prediction, not a clinical call.

BICD2 p.Arg581His

c.1742G>A · rs201771783 · VCV859617

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1263 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0125%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1263	likely benign
REVEL	0.124	moderately benign-leaning
SaProt	LLR -7.27	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -1.8, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 3,839 bp · p 5.4e-09 · regional, not allelic
Overall
CADD	17.6	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 0.0125% European (non-Finnish) · 147/1,172,802 alleles

Filtering AF 0.0109% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0102%

Overall 0.0101% 162/1,596,898 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0125%	7,978
Admixed American	0.0121%	8,238
Remaining individualsnot grpmax-eligible	0.00808%	12,374
African / African-American	0.00401%	24,923

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.Arg581His
Coding: c.1742G>A
MANE Select: NM_001003800
dbSNP: rs201771783
Type: single nucleotide variant
Location: chr9:92718903 (GRCh38)
Gene constraint: LOEUF 0.507 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 78.89 · 2 PDB
Residue 581: the 'interaction with kif5a' region; the 'disordered' region

Full BICD2 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

Also linked: autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures

Similar variants

BICD2 p.Arg581Ser Uncertain significance ★★ ⚠ same residue
BICD2 p.Arg581Cys Likely benign ★★ ⚠ same residue
BICD2 p.Arg694Cys Pathogenic/Likely pathogenic ★★ same condition
BICD2 p.Arg694Gly Pathogenic/Likely pathogenic ★★ same condition
BICD2 p.Lys734Glu Likely pathogenic ★★ same condition
BICD2 p.Ser107Leu Pathogenic ★★ ⚠ same condition
BICD2 p.Thr703Met Pathogenic/Likely pathogenic ★★ same condition
BICD2 p.Tyr538Cys Pathogenic ★★ ⚠ 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-arg581his (accessed [today's date]).

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