Is DYNC2H1 p.Phe1849fs (c.5547del) pathogenic?

DYNC2H1 p.Phe1849fs (c.5547del) is classified Pathogenic/Likely pathogenic in DYNC2H1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-02-12). Very rare (popmax 0.00103%, nfe); Associated with Jeune syndrome.

What condition is associated with DYNC2H1 p.Phe1849fs (c.5547del)?

DYNC2H1 p.Phe1849fs (c.5547del) is associated with Jeune syndrome, asphyxiating thoracic dystrophy 3 (ClinVar).

How common is DYNC2H1 p.Phe1849fs (c.5547del) in the general population?

DYNC2H1 p.Phe1849fs (c.5547del) is very rare (popmax 0.00103%, nfe) (gnomAD).

DYNC2H1 p.Phe1849fs

c.5547del · rs771003300 · VCV407162

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00103%, nfe)

Conditions

Jeune syndrome

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 35 of 89
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.2	GERP 1.9, phastCons 1
Overall
CADD	33.0	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 0.00103% European (non-Finnish) · 12/1,161,740 alleles

Filtering AF 0.000551% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000435%

Overall 0.000827% 13/1,572,194 alleles · very rare exomes 11/1,420,206 · genomes 2/151,988 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00165%	60,690
European (non-Finnish)grpmax	0.00103%	96,812

Remaining individuals 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: DYNC2H1
Protein: p.Phe1849fs
Coding: c.5547del
MANE Select: NM_001377
dbSNP: rs771003300
Type: Deletion
Location: chr11:103173294 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1849: an α-helix; the 'aaa 1' region

Full DYNC2H1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Jeune syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: asphyxiating thoracic dystrophy 3

Similar variants

DYNC2H1 c.1360+2del Pathogenic/Likely pathogenic ★★ same condition
DYNC2H1 p.Arg1881fs Pathogenic/Likely pathogenic ★★ same condition
DYNC2H1 p.Asn1495fs Pathogenic/Likely pathogenic ★★ same condition
DYNC2H1 p.Asp4156fs Pathogenic ★★ same condition
DYNC2H1 p.Gln1566fs Pathogenic/Likely pathogenic ★★ same condition
DYNC2H1 p.Glu1949fs Pathogenic ★★ same condition
DYNC2H1 p.His1896fs Pathogenic ★★ same condition
DYNC2H1 p.Ile4057fs 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/dync2h1-p-phe1849fs (accessed [today's date]).

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