Is DYNC2H1 p.Pro3729Ser (c.11185C>T) pathogenic?

DYNC2H1 p.Pro3729Ser (c.11185C>T) is classified Conflicting classifications of pathogenicity in DYNC2H1 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.161); Ultra-rare (popmax 0.0354%, nfe); Associated with Jeune syndrome.

What condition is associated with DYNC2H1 p.Pro3729Ser (c.11185C>T)?

DYNC2H1 p.Pro3729Ser (c.11185C>T) is associated with Jeune syndrome, asphyxiating thoracic dystrophy 3, inherited retinal dystrophy (ClinVar).

How common is DYNC2H1 p.Pro3729Ser (c.11185C>T) in the general population?

DYNC2H1 p.Pro3729Ser (c.11185C>T) is ultra-rare (popmax 0.0354%, nfe) (gnomAD).

What do computational predictors say about DYNC2H1 p.Pro3729Ser (c.11185C>T)?

AlphaMissense predicts likely benign (score 0.161) — an in-silico prediction, not a clinical call.

DYNC2H1 p.Pro3729Ser

c.11185C>T · rs199766341 · VCV878868

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.161 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0354%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Jeune syndrome

Computational evidence

Protein change
AlphaMissense	0.161	likely benign
REVEL	0.138	moderately 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 5.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 293 kb · p 0.28 · regional, not allelic
Overall
CADD	26.0	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 0.0354% European (non-Finnish) · 417/1,179,056 alleles

Filtering AF 0.0325% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0314%

Overall 0.03% 483/1,612,518 alleles · ultra-rare exomes 465/1,460,512 · genomes 18/152,006 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0913%	1,095
Remaining individualsnot grpmax-eligible	0.0368%	2,714
European (non-Finnish)grpmax	0.0354%	2,827
Admixed American	0.0167%	5,990
African / African-American	0.00668%	14,966
South Asian	0.0011%	90,958

Ashkenazi Jewish 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.Pro3729Ser
Coding: c.11185C>T
MANE Select: NM_001377
dbSNP: rs199766341
Type: single nucleotide variant
Location: chr11:103303182 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 3729: the 'aaa 6' 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

Also linked: asphyxiating thoracic dystrophy 3 inherited retinal dystrophy

Similar variants

DYNC2H1 p.Pro3729Leu Likely pathogenic ★ same residue
DYNC2H1 p.Pro3729Thr 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-pro3729ser (accessed [today's date]).

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