Is DYNC2I2 p.Thr514fs (c.1541_1542del) pathogenic?

DYNC2I2 p.Thr514fs (c.15411542del) is classified Likely pathogenic in DYNC2I2 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-12-28). Very rare (popmax 0.00534%, afr); Associated with WDR34-related disorders.

What condition is associated with DYNC2I2 p.Thr514fs (c.1541_1542del)?

DYNC2I2 p.Thr514fs (c.1541_1542del) is associated with WDR34-related disorders, short-rib thoracic dysplasia 11 with or without polydactyly (ClinVar).

How common is DYNC2I2 p.Thr514fs (c.1541_1542del) in the general population?

DYNC2I2 p.Thr514fs (c.1541_1542del) is very rare (popmax 0.00534%, afr) (gnomAD).

DYNC2I2 p.Thr514fs

c.1541_1542del · rs431905519 · VCV97043

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Conditions

WDR34-related disorders

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 3.3	GERP 1.7, phastCons 1
Overall
CADD	25.7	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 0.00534% African / African-American · 4/74,944 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000806% 13/1,613,458 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,736
Finnishnot grpmax-eligible	0.00316%	31,693
South Asian	0.0022%	45,545
European (non-Finnish)	0.000424%	236,009

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.Thr514fs
Coding: c.1541_1542del
MANE Select: NM_052844
dbSNP: rs431905519
Type: Microsatellite
Location: chr9:128633813 (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

WDR34-related disorders

Also linked: short-rib thoracic dysplasia 11 with or without polydactyly

Similar variants

DYNC2I2 p.Thr514Ile Uncertain significance ★ ⚠ same residue
DYNC2I2 p.Glu368fs Pathogenic/Likely pathogenic ★★ same condition
DYNC2I2 p.Arg373fs Pathogenic ★ same condition
DYNC2I2 p.Thr473fs 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-thr514fs (accessed [today's date]).

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