Is DYNC2H1 p.Leu592Phe (c.1774C>T) pathogenic?

DYNC2H1 p.Leu592Phe (c.1774C>T) is classified Conflicting classifications of pathogenicity in DYNC2H1 (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2025-07-22). AlphaMissense: likely benign (0.1286); Rare (popmax 0.314%, mid); Associated with Jeune syndrome.

What condition is associated with DYNC2H1 p.Leu592Phe (c.1774C>T)?

DYNC2H1 p.Leu592Phe (c.1774C>T) is associated with Jeune syndrome, intellectual disability, asphyxiating thoracic dystrophy 3 (ClinVar).

How common is DYNC2H1 p.Leu592Phe (c.1774C>T) in the general population?

DYNC2H1 p.Leu592Phe (c.1774C>T) is rare (popmax 0.314%, mid) (gnomAD).

What do computational predictors say about DYNC2H1 p.Leu592Phe (c.1774C>T)?

AlphaMissense predicts likely benign (score 0.1286) — an in-silico prediction, not a clinical call.

DYNC2H1 p.Leu592Phe

c.1774C>T · rs180861816 · VCV216489

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.1286 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.314%, mid)

Conditions

Jeune syndrome

Computational evidence

Protein change
AlphaMissense	0.1286	likely benign
REVEL	0.556	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 1.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 61 kb · p 0.56 · regional, not allelic
Overall
CADD	25.1	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 0.314% Middle Eastern · 19/6,058 alleles

Filtering AF 0.205% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.171%

Overall 0.0203% 328/1,613,478 alleles · rare exomes 257/1,461,204 · genomes 71/152,274 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.314%	319
African / African-American	0.096%	1,042
Admixed American	0.0717%	1,394
Remaining individualsnot grpmax-eligible	0.0416%	2,402
European (non-Finnish)	0.0139%	7,193
South Asian	0.0044%	22,750

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.Leu592Phe
Coding: c.1774C>T
MANE Select: NM_001377
dbSNP: rs180861816
Type: single nucleotide variant
Location: chr11:103125212 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 592: the 'stem' 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: intellectual disability asphyxiating thoracic dystrophy 3

Similar variants

DYNC2H1 p.Leu592His 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
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-leu592phe (accessed [today's date]).

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