Is DYNC2H1 p.Arg587Cys (c.1759C>T) pathogenic?

DYNC2H1 p.Arg587Cys (c.1759C>T) is classified Pathogenic/Likely pathogenic in DYNC2H1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-02-12). AlphaMissense: likely pathogenic (0.6317); Very rare (popmax 0.00134%, afr); Associated with DYNC2H1-related disorder.

What condition is associated with DYNC2H1 p.Arg587Cys (c.1759C>T)?

DYNC2H1 p.Arg587Cys (c.1759C>T) is associated with DYNC2H1-related disorder, asphyxiating thoracic dystrophy 3, Jeune syndrome (ClinVar).

How common is DYNC2H1 p.Arg587Cys (c.1759C>T) in the general population?

DYNC2H1 p.Arg587Cys (c.1759C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about DYNC2H1 p.Arg587Cys (c.1759C>T)?

AlphaMissense predicts likely pathogenic (score 0.6317) — an in-silico prediction, not a clinical call.

DYNC2H1 p.Arg587Cys

c.1759C>T · rs137853030 · VCV6506

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.6317 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

DYNC2H1-related disorder

Computational evidence

Protein change
AlphaMissense	0.6317	likely pathogenic ✓ concordant with ClinVar
REVEL	0.632	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 61 kb · p 0.56 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,888 alleles

Overall 0.000124% 2/1,613,334 alleles · very rare exomes 1/1,461,234 · genomes 1/152,100 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,434
African / African-Americangrpmax	0.00134%	74,888

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.Arg587Cys
Coding: c.1759C>T
MANE Select: NM_001377
dbSNP: rs137853030
Type: single nucleotide variant
Location: chr11:103125197 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 587: the 'stem' region; a UniProt-annotated variant site (in srtd3)

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

Disease context

Also linked: asphyxiating thoracic dystrophy 3 Jeune syndrome

Similar variants

DYNC2H1 p.Arg587His Likely pathogenic ★ same residue
DYNC2H1 p.Arg587Leu Uncertain significance ★ ⚠ 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

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-arg587cys (accessed [today's date]).

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