Is DYNC2H1 p.Arg1253= (c.3757C>A) pathogenic?

DYNC2H1 p.Arg1253= (c.3757C>A) is classified Uncertain significance in DYNC2H1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-10-23). Very rare (popmax 0.00501%, amr); Associated with Jeune syndrome.

What condition is associated with DYNC2H1 p.Arg1253= (c.3757C>A)?

DYNC2H1 p.Arg1253= (c.3757C>A) is associated with Jeune syndrome (ClinVar).

How common is DYNC2H1 p.Arg1253= (c.3757C>A) in the general population?

DYNC2H1 p.Arg1253= (c.3757C>A) is very rare (popmax 0.00501%, amr) (gnomAD).

DYNC2H1 p.Arg1253=

c.3757C>A · rs375636006 · VCV1902555

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00501%, amr)

Conditions

Jeune syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.22	acceptor loss, 12 bp away · masked 0 · deltas
Pangolin	Δ0.23	loss · gain 0.03 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Overall
CADD	9.415	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00501% Admixed American · 3/59,836 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000669%

Overall 0.000496% 8/1,612,544 alleles · very rare exomes 8/1,460,580 · genomes 0/151,964 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00501%	19,945
Remaining individualsnot grpmax-eligible	0.0016%	62,442
European (non-Finnish)	0.000339%	294,855

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.Arg1253=
Coding: c.3757C>A
MANE Select: NM_001377
dbSNP: rs375636006
Type: single nucleotide variant
Location: chr11:103156400 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1253: 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.Arg1253Trp Uncertain significance ★ same residue
DYNC2H1 p.Arg1253Gln 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-arg1253 (accessed [today's date]).

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