Is DYNC2H1 p.Pro4042Ser (c.12124C>T) pathogenic?

DYNC2H1 p.Pro4042Ser (c.12124C>T) is classified Uncertain significance in DYNC2H1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-03). AlphaMissense: likely pathogenic (0.7366); Very rare (popmax 0.0012%, nfe); Associated with Jeune syndrome.

What condition is associated with DYNC2H1 p.Pro4042Ser (c.12124C>T)?

DYNC2H1 p.Pro4042Ser (c.12124C>T) is associated with Jeune syndrome (ClinVar).

How common is DYNC2H1 p.Pro4042Ser (c.12124C>T) in the general population?

DYNC2H1 p.Pro4042Ser (c.12124C>T) is very rare (popmax 0.0012%, nfe) (gnomAD).

What do computational predictors say about DYNC2H1 p.Pro4042Ser (c.12124C>T)?

AlphaMissense predicts likely pathogenic (score 0.7366) — an in-silico prediction, not a clinical call.

DYNC2H1 p.Pro4042Ser

c.12124C>T · VCV4705669

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7366 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0012%, nfe)

Conditions

Jeune syndrome

Computational evidence

Protein change
AlphaMissense	0.7366	likely pathogenic
REVEL	0.425	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 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 293 kb · p 0.28 · regional, not allelic
Overall
CADD	25.8	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 0.0012% European (non-Finnish) · 14/1,163,070 alleles

Filtering AF 0.000698% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000546%

Overall 0.00101% 16/1,583,426 alleles · very rare exomes 16/1,431,214 · genomes 0/152,212 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00325%	30,724
European (non-Finnish)grpmax	0.0012%	83,076

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.Pro4042Ser
Coding: c.12124C>T
MANE Select: NM_001377
Type: single nucleotide variant
Location: chr11:103358327 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 4042: an α-helix

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-pro4042ser (accessed [today's date]).

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