Is BICD2 p.Ser780Leu (c.2339C>T) pathogenic?

BICD2 p.Ser780Leu (c.2339C>T) is classified Conflicting classifications of pathogenicity in BICD2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-19). AlphaMissense: likely pathogenic (0.564); Very rare (popmax 0.00662%, nfe); Associated with Inborn genetic diseases.

What condition is associated with BICD2 p.Ser780Leu (c.2339C>T)?

BICD2 p.Ser780Leu (c.2339C>T) is associated with Inborn genetic diseases, autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures (ClinVar).

How common is BICD2 p.Ser780Leu (c.2339C>T) in the general population?

BICD2 p.Ser780Leu (c.2339C>T) is very rare (popmax 0.00662%, nfe) (gnomAD).

What do computational predictors say about BICD2 p.Ser780Leu (c.2339C>T)?

AlphaMissense predicts likely pathogenic (score 0.564) — an in-silico prediction, not a clinical call.

BICD2 p.Ser780Leu

c.2339C>T · rs377454040 · VCV950283

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.564 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00662%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.564	likely pathogenic
REVEL	0.397	indeterminate
SaProt	LLR -12.43	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 2.5, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 3,839 bp · p 5.4e-09 · 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 0.00662% European (non-Finnish) · 78/1,178,784 alleles

Filtering AF 0.00539% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00498%

Overall 0.00548% 80/1,459,524 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00662%	15,113
East Asian	0.00223%	44,834
Remaining individualsnot grpmax-eligible	0.0016%	62,430

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.Ser780Leu
Coding: c.2339C>T
MANE Select: NM_001003800
dbSNP: rs377454040
Type: single nucleotide variant
Location: chr9:92715383 (GRCh38)
Gene constraint: LOEUF 0.507 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 78.89 · 2 PDB
Residue 780: an α-helix; the 'interaction with ranbp2' region; the 'interacts with rab6a' 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.Ser780= 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
BICD2 p.Tyr556Ser Likely 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-ser780leu (accessed [today's date]).

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