Is DYNC2I1 p.Asp126fs (c.378_381del) pathogenic?

DYNC2I1 p.Asp126fs (c.378381del) is classified Pathogenic in DYNC2I1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-06). Very rare (popmax 0.000174%, nfe); Associated with short-rib thoracic dysplasia 8 with or without polydactyly.

What condition is associated with DYNC2I1 p.Asp126fs (c.378_381del)?

DYNC2I1 p.Asp126fs (c.378_381del) is associated with short-rib thoracic dysplasia 8 with or without polydactyly (ClinVar).

How common is DYNC2I1 p.Asp126fs (c.378_381del) in the general population?

DYNC2I1 p.Asp126fs (c.378_381del) is very rare (popmax 0.000174%, nfe) (gnomAD).

DYNC2I1 p.Asp126fs

c.378_381del · rs1203407896 · VCV2025330

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000174%, nfe)

Conditions

short-rib thoracic dysplasia 8 with or without polydactyly

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 25
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.084	GERP -3

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000174% European (non-Finnish) · 2/1,146,952 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000129% 2/1,550,980 alleles · very rare exomes 2/1,398,682 · genomes 0/152,298 · joint denominator

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: DYNC2I1
Protein: p.Asp126fs
Coding: c.378_381del
MANE Select: NM_018051
dbSNP: rs1203407896
Type: Deletion
Location: chr7:158871447 (GRCh38)
Gene constraint: LOEUF 0.802 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 62.87 · 4 PDB
Residue 126: the 'disordered' region

Full DYNC2I1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

short-rib thoracic dysplasia 8 with or without polydactyly — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DYNC2I1 p.Lys105del Benign ★★ same condition
DYNC2I1 p.Asn522fs Likely pathogenic ★ same condition
DYNC2I1 p.Asp224fs Pathogenic ★ same condition
DYNC2I1 p.Cys388fs Likely pathogenic ★ same condition
DYNC2I1 c.2257+5del Uncertain significance ★ same condition
DYNC2I1 p.Gln947fs Uncertain significance ★ same condition
DYNC2I1 c.1703-13del Likely benign ★ same condition
DYNC2I1 c.1922-4del Benign ★ 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/dync2i1-p-asp126fs (accessed [today's date]).

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