Is DYNC2H1 p.Arg684Trp (c.2050C>T) pathogenic?

DYNC2H1 p.Arg684Trp (c.2050C>T) is classified Uncertain significance in DYNC2H1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-17). AlphaMissense: likely benign (0.2067); Ultra-rare (popmax 0.0165%, mid); Associated with Jeune syndrome.

What condition is associated with DYNC2H1 p.Arg684Trp (c.2050C>T)?

DYNC2H1 p.Arg684Trp (c.2050C>T) is associated with Jeune syndrome (ClinVar).

How common is DYNC2H1 p.Arg684Trp (c.2050C>T) in the general population?

DYNC2H1 p.Arg684Trp (c.2050C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about DYNC2H1 p.Arg684Trp (c.2050C>T)?

AlphaMissense predicts likely benign (score 0.2067) — an in-silico prediction, not a clinical call.

DYNC2H1 p.Arg684Trp

c.2050C>T · rs529152317 · VCV1985174

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2067 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Jeune syndrome

Computational evidence

Protein change
AlphaMissense	0.2067	likely benign
REVEL	0.264	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.21	GERP -0.96, phastCons 0.89
Regional constraint	o/e 0.99	unconstrained · MANE · 61 kb · p 0.56 · regional, not allelic
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,056 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.0018% 29/1,613,070 alleles · ultra-rare exomes 27/1,460,852 · genomes 2/152,218 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,056
European (non-Finnish)	0.00203%	49,149
Admixed American	0.00167%	59,860
Remaining individualsnot grpmax-eligible	0.0016%	62,456
Finnishnot grpmax-eligible	0.00156%	63,972
South Asian	0.0011%	90,878

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.Arg684Trp
Coding: c.2050C>T
MANE Select: NM_001377
dbSNP: rs529152317
Type: single nucleotide variant
Location: chr11:103133651 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 684: 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 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
DYNC2H1 c.12457-1G>C 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-arg684trp (accessed [today's date]).

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