Is BICD2 p.Arg214Cys (c.640C>T) pathogenic?

BICD2 p.Arg214Cys (c.640C>T) is classified Conflicting classifications of pathogenicity in BICD2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-13). AlphaMissense: likely benign (0.2208); Very rare (popmax 0.00329%, sas); Associated with autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures.

How common is BICD2 p.Arg214Cys (c.640C>T) in the general population?

BICD2 p.Arg214Cys (c.640C>T) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about BICD2 p.Arg214Cys (c.640C>T)?

AlphaMissense predicts likely benign (score 0.2208) — an in-silico prediction, not a clinical call.

BICD2 p.Arg214Cys

Q: What condition is associated with BICD2 p.Arg214Cys (c.640C>T)?

BICD2 p.Arg214Cys (c.640C>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.640C>T · rs201293367 · VCV474279

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2208 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures

Computational evidence

Protein change
AlphaMissense	0.2208	likely benign
REVEL	0.436	indeterminate
SaProt	LLR -8.92	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 6.5	GERP 2.4, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 1,691 bp · p 0.0012 · 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 0.00329% South Asian · 3/91,086 alleles

Filtering AF 0.00207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00254% 41/1,613,938 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,828
South Asiangrpmax	0.00329%	30,362
European (non-Finnish)	0.00288%	34,706
African / African-American	0.00133%	74,916

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg214Cys
Coding: c.640C>T
MANE Select: NM_001003800
dbSNP: rs201293367
Type: single nucleotide variant
Location: chr9:92720722 (GRCh38)
Gene constraint: LOEUF 0.507 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 78.89 · 2 PDB
Residue 214: the 'interacts with dynll1, dync1h1, dync1i2, dctn1 and dctn2' 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.Arg214His Conflicting classifications of pathogenicity ★ ⚠ same residue
BICD2 p.Arg214Leu 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-arg214cys (accessed [today's date]).

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