Is BICD2 p.Arg566Cys (c.1696C>T) pathogenic?

BICD2 p.Arg566Cys (c.1696C>T) is classified Conflicting classifications of pathogenicity in BICD2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-03-03). AlphaMissense: likely benign (0.1273); Ultra-rare (popmax 0.0341%, sas); Associated with BICD2-related disorder.

What condition is associated with BICD2 p.Arg566Cys (c.1696C>T)?

BICD2 p.Arg566Cys (c.1696C>T) is associated with BICD2-related disorder, autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures (ClinVar).

How common is BICD2 p.Arg566Cys (c.1696C>T) in the general population?

BICD2 p.Arg566Cys (c.1696C>T) is ultra-rare (popmax 0.0341%, sas) (gnomAD).

What do computational predictors say about BICD2 p.Arg566Cys (c.1696C>T)?

AlphaMissense predicts likely benign (score 0.1273) — an in-silico prediction, not a clinical call.

BICD2 p.Arg566Cys

c.1696C>T · rs748022488 · VCV570965

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1273 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0341%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

BICD2-related disorder

Computational evidence

Protein change
AlphaMissense	0.1273	likely benign
REVEL	0.166	moderately benign-leaning
SaProt	LLR -10.85	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 1.3, phastCons 1
Regional constraint	o/e 0.72	unconstrained · MANE · 3,839 bp · p 5.4e-09 · regional, not allelic
Overall
CADD	21.3	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 0.0341% South Asian · 31/91,032 alleles

Filtering AF 0.0246% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0214%

Overall 0.00578% 93/1,609,296 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0341%	2,937
Remaining individualsnot grpmax-eligible	0.00802%	12,465
European (non-Finnish)	0.00432%	23,131
African / African-American	0.00401%	24,952
Finnishnot grpmax-eligible	0.00329%	30,424
Admixed American	0.00167%	59,966

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.Arg566Cys
Coding: c.1696C>T
MANE Select: NM_001003800
dbSNP: rs748022488
Type: single nucleotide variant
Location: chr9:92718949 (GRCh38)
Gene constraint: LOEUF 0.507 · pLI 0.95 (gnomAD)
Structure: AlphaFold pLDDT 78.89 · 2 PDB
Residue 566: the 'interaction with kif5a' region; the 'disordered' region

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

Disease context

BICD2-related disorder

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

Similar variants

BICD2 p.Arg566Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
BICD2 p.Arg566His 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

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-arg566cys (accessed [today's date]).

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