Is DYNC2I2 p.Thr473fs (c.1418_1419del) pathogenic?

DYNC2I2 p.Thr473fs (c.14181419del) is classified Likely pathogenic in DYNC2I2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-13). Very rare (popmax 0.00891%, eas); Associated with short-rib thoracic dysplasia 11 with or without polydactyly.

What condition is associated with DYNC2I2 p.Thr473fs (c.1418_1419del)?

DYNC2I2 p.Thr473fs (c.1418_1419del) is associated with short-rib thoracic dysplasia 11 with or without polydactyly (ClinVar).

How common is DYNC2I2 p.Thr473fs (c.1418_1419del) in the general population?

DYNC2I2 p.Thr473fs (c.1418_1419del) is very rare (popmax 0.00891%, eas) (gnomAD).

DYNC2I2 p.Thr473fs

c.1418_1419del · rs755570414 · VCV1068136

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Conditions

short-rib thoracic dysplasia 11 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	escapes	premature termination codon in the last exon (9 of 9) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1	GERP -2, phastCons 0.021
Overall
CADD	28.9	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00891% East Asian · 4/44,902 alleles

Filtering AF 0.00563% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.00676% 109/1,613,068 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0159%	6,299
Remaining individualsnot grpmax-eligible	0.0112%	8,925
East Asiangrpmax	0.00891%	11,225
European (non-Finnish)	0.00686%	14,569
Admixed American	0.00667%	15,001
African / African-American	0.00267%	37,471
South Asian	0.0011%	91,092

Finnish 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: DYNC2I2
Protein: p.Thr473fs
Coding: c.1418_1419del
MANE Select: NM_052844
dbSNP: rs755570414
Type: Microsatellite
Location: chr9:128633936 (GRCh38)
Gene constraint: LOEUF 1.036 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.66 · 4 PDB

Full DYNC2I2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

short-rib thoracic dysplasia 11 with or without polydactyly — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DYNC2I2 p.Thr473Pro Uncertain significance ★ ⚠ same residue
DYNC2I2 p.Glu368fs Pathogenic/Likely pathogenic ★★ same condition
DYNC2I2 p.Arg373fs Pathogenic ★ same condition
DYNC2I2 p.Thr514fs Likely pathogenic ★ same condition
DYNC2I2 p.Val398fs Pathogenic ★ same condition
DYNC2I2 p.Gln144dup Uncertain significance ★ same condition
DYNC2I2 c.1373-12CT[2] Likely benign ★ same condition
DYNC2I2 c.1372+1G>A Pathogenic/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/dync2i2-p-thr473fs (accessed [today's date]).

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