Is BICD2 p.His540= (c.1620C>T) pathogenic?

BICD2 p.His540= (c.1620C>T) is classified Likely benign in BICD2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-29). Ultra-rare (popmax 0.0339%, mid); Associated with autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures.

How common is BICD2 p.His540= (c.1620C>T) in the general population?

BICD2 p.His540= (c.1620C>T) is ultra-rare (popmax 0.0339%, mid) (gnomAD).

BICD2 p.His540=

Q: What condition is associated with BICD2 p.His540= (c.1620C>T)?

BICD2 p.His540= (c.1620C>T) is associated with autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures (ClinVar).

Q: How is Autosomal dominant childhood-onset proximal spinal muscular atrophy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.1620C>T · rs375331979 · VCV391334

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0339%, mid)

Conditions

autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.1	GERP -5
Overall
CADD	0.698	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0339% Middle Eastern · 2/5,894 alleles

Filtering AF 0.0265% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0256%

Overall 0.0228% 368/1,612,478 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0339%	2,947
European (non-Finnish)	0.0292%	3,430
Remaining individualsnot grpmax-eligible	0.0176%	5,678
African / African-American	0.00666%	15,010
Admixed American	0.005%	20,011
South Asian	0.0022%	45,537
Finnishnot grpmax-eligible	0.0016%	62,624

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.His540=
Coding: c.1620C>T
MANE Select: NM_001003800
dbSNP: rs375331979
Type: single nucleotide variant
Location: chr9:92719025 (GRCh38)
Gene constraint: LOEUF 0.507 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 78.89 · 2 PDB
Residue 540: the 'interaction with kif5a' region

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

Disease context

autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal dominant childhood-onset proximal spinal muscular atrophy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Antenatal, Childhood, Infancy, Neonatal
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

BICD2 p.His540Asp Uncertain significance ★ ⚠ same residue
BICD2 p.His540Arg Uncertain significance ★ ⚠ same residue
BICD2 p.Arg694Cys 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.Tyr556Ser Likely pathogenic ★★ ⚠ same condition
BICD2 c.1062+5G>A 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-his540 (accessed [today's date]).

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