Is DYNC2H1 p.Ala1995Val (c.5984C>T) pathogenic?

DYNC2H1 p.Ala1995Val (c.5984C>T) is classified Pathogenic/Likely pathogenic in DYNC2H1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-22). AlphaMissense: likely pathogenic (0.6498); Very rare (popmax 0.00446%, eas); Associated with Jeune syndrome.

What condition is associated with DYNC2H1 p.Ala1995Val (c.5984C>T)?

DYNC2H1 p.Ala1995Val (c.5984C>T) is associated with Jeune syndrome, asphyxiating thoracic dystrophy 3 (ClinVar).

How common is DYNC2H1 p.Ala1995Val (c.5984C>T) in the general population?

DYNC2H1 p.Ala1995Val (c.5984C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about DYNC2H1 p.Ala1995Val (c.5984C>T)?

AlphaMissense predicts likely pathogenic (score 0.6498) — an in-silico prediction, not a clinical call.

DYNC2H1 p.Ala1995Val

c.5984C>T · rs963717773 · VCV446619

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.6498 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

Jeune syndrome

Computational evidence

Protein change
AlphaMissense	0.6498	likely pathogenic ✓ concordant with ClinVar
REVEL	0.331	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 8,693 bp · p 6.7e-06 · regional, not allelic
Overall
CADD	26.7	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 0.00446% East Asian · 2/44,802 alleles

Filtering AF 0.00074% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000744% 12/1,613,000 alleles · very rare exomes 11/1,460,988 · genomes 1/152,012 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,401
Finnishnot grpmax-eligible	0.00156%	63,960
European (non-Finnish)	0.000763%	131,065

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.Ala1995Val
Coding: c.5984C>T
MANE Select: NM_001377
dbSNP: rs963717773
Type: single nucleotide variant
Location: chr11:103177665 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1995: an α-helix; the 'aaa 2' 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 p.Ala1995Thr Pathogenic/Likely pathogenic ★★ same residue
DYNC2H1 p.Ala1995= 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

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-ala1995val (accessed [today's date]).

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