Is DYNC2H1 p.Arg3489Trp (c.10465C>T) pathogenic?

DYNC2H1 p.Arg3489Trp (c.10465C>T) is classified Uncertain significance in DYNC2H1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-10). AlphaMissense: likely pathogenic (0.7808); Ultra-rare (popmax 0.0132%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DYNC2H1 p.Arg3489Trp (c.10465C>T)?

DYNC2H1 p.Arg3489Trp (c.10465C>T) is associated with Inborn genetic diseases, Jeune syndrome (ClinVar).

How common is DYNC2H1 p.Arg3489Trp (c.10465C>T) in the general population?

DYNC2H1 p.Arg3489Trp (c.10465C>T) is ultra-rare (popmax 0.0132%, nfe) (gnomAD).

What do computational predictors say about DYNC2H1 p.Arg3489Trp (c.10465C>T)?

AlphaMissense predicts likely pathogenic (score 0.7808) — an in-silico prediction, not a clinical call.

DYNC2H1 p.Arg3489Trp

c.10465C>T · rs376682072 · VCV1987423

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7808 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0132%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7808	likely pathogenic
REVEL	0.444	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 2.1	GERP 1.1, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 293 kb · p 0.28 · regional, not allelic
Overall
CADD	25.3	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 0.0132% European (non-Finnish) · 155/1,177,316 alleles

Filtering AF 0.0114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0108%

Overall 0.0109% 175/1,609,362 alleles · ultra-rare exomes 166/1,457,186 · genomes 9/152,176 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0177%	5,663
European (non-Finnish)grpmax	0.0132%	7,596
African / African-American	0.00803%	12,460
South Asian	0.00222%	45,100
Admixed American	0.00167%	59,750

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg3489Trp
Coding: c.10465C>T
MANE Select: NM_001377
dbSNP: rs376682072
Type: single nucleotide variant
Location: chr11:103257611 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 3489: an α-helix

Full DYNC2H1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Jeune syndrome

Similar variants

DYNC2H1 p.Arg3489Gln Uncertain significance ★ same residue
DYNC2H1 p.Arg3489Leu 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-arg3489trp (accessed [today's date]).

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