Is DYNC2H1 p.Leu4232Arg (c.12695T>G) pathogenic?

DYNC2H1 p.Leu4232Arg (c.12695T>G) is classified Pathogenic in DYNC2H1 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-07-14). AlphaMissense: likely pathogenic (0.9653); Very rare (popmax 0.000509%, nfe); Associated with Jeune syndrome.

What condition is associated with DYNC2H1 p.Leu4232Arg (c.12695T>G)?

DYNC2H1 p.Leu4232Arg (c.12695T>G) is associated with Jeune syndrome (ClinVar).

How common is DYNC2H1 p.Leu4232Arg (c.12695T>G) in the general population?

DYNC2H1 p.Leu4232Arg (c.12695T>G) is very rare (popmax 0.000509%, nfe) (gnomAD).

What do computational predictors say about DYNC2H1 p.Leu4232Arg (c.12695T>G)?

AlphaMissense predicts likely pathogenic (score 0.9653) — an in-silico prediction, not a clinical call.

DYNC2H1 p.Leu4232Arg

c.12695T>G · rs1945272232 · VCV978201

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9653 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Conditions

Jeune syndrome

Computational evidence

Protein change
AlphaMissense	0.9653	likely pathogenic ✓ concordant with ClinVar · top 7% in DYNC2H1
REVEL	0.535	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 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 293 kb · p 0.28 · 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 0.000509% European (non-Finnish) · 6/1,179,760 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,613,804 alleles · very rare exomes 6/1,461,448 · genomes 0/152,356 · 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.Leu4232Arg
Coding: c.12695T>G
MANE Select: NM_001377
dbSNP: rs1945272232
Type: single nucleotide variant
Location: chr11:103468635 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 4232: a β-strand; a UniProt-annotated variant site (in srtd3)

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-leu4232arg (accessed [today's date]).

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