Is BICD2 p.Glu65Lys (c.193G>A) pathogenic?

BICD2 p.Glu65Lys (c.193G>A) is classified Uncertain significance in BICD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-15). AlphaMissense: ambiguous (0.5575); Absent from gnomAD v4.1; Associated with autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures.

How common is BICD2 p.Glu65Lys (c.193G>A) in the general population?

BICD2 p.Glu65Lys (c.193G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BICD2 p.Glu65Lys (c.193G>A)?

AlphaMissense predicts ambiguous (score 0.5575) — an in-silico prediction, not a clinical call.

BICD2 p.Glu65Lys

Q: What condition is associated with BICD2 p.Glu65Lys (c.193G>A)?

BICD2 p.Glu65Lys (c.193G>A) 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.193G>A · VCV3684110

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5575 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,549,022)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures

Computational evidence

Protein change
AlphaMissense	0.5575	ambiguous
REVEL	0.126	moderately benign-leaning
SaProt	LLR -9.61	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.2	GERP 1.8, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 42 kb · p 0.00095 · regional, not allelic
Overall
CADD	28.6	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

No allele count reported in gnomAD v4.1 (AN 1,549,022). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: BICD2
Protein: p.Glu65Lys
Coding: c.193G>A
MANE Select: NM_001003800
Type: single nucleotide variant
Location: chr9:92764552 (GRCh38)
Gene constraint: LOEUF 0.507 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 78.89 · 2 PDB
Residue 65: the 'interacts with dynll1, dync1h1, dync1i2, dctn1 and dctn2' region; an α-helix

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.Glu65= Likely benign ★ 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
BICD2 p.Ala326Pro 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-glu65lys (accessed [today's date]).

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