Is DYNC2H1 p.Leu1234Phe (c.3700C>T) pathogenic?

DYNC2H1 p.Leu1234Phe (c.3700C>T) is classified Uncertain significance in DYNC2H1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-06). AlphaMissense: ambiguous (0.3568); Very rare (popmax 8.48e-05%, nfe); Associated with Jeune syndrome.

What condition is associated with DYNC2H1 p.Leu1234Phe (c.3700C>T)?

DYNC2H1 p.Leu1234Phe (c.3700C>T) is associated with Jeune syndrome (ClinVar).

How common is DYNC2H1 p.Leu1234Phe (c.3700C>T) in the general population?

DYNC2H1 p.Leu1234Phe (c.3700C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about DYNC2H1 p.Leu1234Phe (c.3700C>T)?

AlphaMissense predicts ambiguous (score 0.3568) — an in-silico prediction, not a clinical call.

DYNC2H1 p.Leu1234Phe

c.3700C>T · rs2134890455 · VCV1355366

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3568 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

Jeune syndrome

Computational evidence

Protein change
AlphaMissense	0.3568	ambiguous
REVEL	0.418	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 61 kb · p 0.56 · regional, not allelic
Overall
CADD	23.9	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 8.48e-05% European (non-Finnish) · 1/1,178,954 alleles

Overall 6.2e-05% 1/1,612,068 alleles · very rare exomes 1/1,460,024 · genomes 0/152,044 · joint denominator

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.Leu1234Phe
Coding: c.3700C>T
MANE Select: NM_001377
dbSNP: rs2134890455
Type: single nucleotide variant
Location: chr11:103155457 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1234: 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

Similar variants

DYNC2H1 p.Leu1234= 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-leu1234phe (accessed [today's date]).

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