Is DYNC2H1 p.Arg456Ter (c.1366C>T) pathogenic?

DYNC2H1 p.Arg456Ter (c.1366C>T) is classified Pathogenic in DYNC2H1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-07). Very rare (popmax 0.00224%, eas); Associated with asphyxiating thoracic dystrophy 3.

What condition is associated with DYNC2H1 p.Arg456Ter (c.1366C>T)?

DYNC2H1 p.Arg456Ter (c.1366C>T) is associated with asphyxiating thoracic dystrophy 3, Jeune syndrome (ClinVar).

How common is DYNC2H1 p.Arg456Ter (c.1366C>T) in the general population?

DYNC2H1 p.Arg456Ter (c.1366C>T) is very rare (popmax 0.00224%, eas) (gnomAD).

DYNC2H1 p.Arg456Ter

c.1366C>T · rs867798254 · VCV2905294

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Conditions

asphyxiating thoracic dystrophy 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 10 of 89
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.6, phastCons 1
Overall
CADD	37.0	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 0.00224% East Asian · 1/44,634 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000376% 6/1,597,764 alleles · very rare exomes 6/1,445,630 · genomes 0/152,134 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,634
Remaining individualsnot grpmax-eligible	0.00162%	61,812
European (non-Finnish)	0.000341%	293,528

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.Arg456Ter
Coding: c.1366C>T
MANE Select: NM_001377
dbSNP: rs867798254
Type: single nucleotide variant
Location: chr11:103121377 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 456: the 'stem' region; a UniProt-annotated variant site (in)

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

Disease context

asphyxiating thoracic dystrophy 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Jeune syndrome

Similar variants

DYNC2H1 p.Arg456Gln Benign/Likely benign ★★ same residue
DYNC2H1 c.10042+2T>G Pathogenic/Likely pathogenic ★★ same condition
DYNC2H1 c.10462-2A>G Likely pathogenic ★★ same condition
DYNC2H1 c.10606-14A>G Pathogenic/Likely pathogenic ★★ same condition
DYNC2H1 c.10695+1G>A Likely pathogenic ★★ same condition
DYNC2H1 c.10813-2A>G Likely pathogenic ★★ same condition
DYNC2H1 c.11493+2T>A Likely pathogenic ★★ same condition
DYNC2H1 c.11650-1G>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/dync2h1-p-arg456ter (accessed [today's date]).

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