Is DYNC2H1 p.Ile486Lys (c.1457T>A) pathogenic?

DYNC2H1 p.Ile486Lys (c.1457T>A) is classified Uncertain significance in DYNC2H1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-09). AlphaMissense: likely pathogenic (0.8981); Absent from gnomAD v4.1; Associated with asphyxiating thoracic dystrophy 3.

What condition is associated with DYNC2H1 p.Ile486Lys (c.1457T>A)?

DYNC2H1 p.Ile486Lys (c.1457T>A) is associated with asphyxiating thoracic dystrophy 3 (ClinVar).

How common is DYNC2H1 p.Ile486Lys (c.1457T>A) in the general population?

DYNC2H1 p.Ile486Lys (c.1457T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DYNC2H1 p.Ile486Lys (c.1457T>A)?

AlphaMissense predicts likely pathogenic (score 0.8981) — an in-silico prediction, not a clinical call.

DYNC2H1 p.Ile486Lys

c.1457T>A · VCV3336266

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8981 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

asphyxiating thoracic dystrophy 3

Computational evidence

Protein change
AlphaMissense	0.8981	likely pathogenic
REVEL	0.807	moderately pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 61 kb · p 0.56 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DYNC2H1
Protein: p.Ile486Lys
Coding: c.1457T>A
MANE Select: NM_001377
Type: single nucleotide variant
Location: chr11:103121468 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 486: the 'stem' region

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

Similar variants

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.12156+1G>A Pathogenic/Likely pathogenic ★★ same condition
DYNC2H1 c.12457-1G>C Likely pathogenic ★★ same condition
DYNC2H1 c.1662-2A>G Likely pathogenic ★★ same condition
DYNC2H1 c.2106+2T>C Likely pathogenic ★★ same condition
DYNC2H1 c.2574+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-ile486lys (accessed [today's date]).

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