Is DYNC2H1 p.Ala1245= (c.3735C>T) pathogenic?

DYNC2H1 p.Ala1245= (c.3735C>T) is classified Conflicting classifications of pathogenicity in DYNC2H1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-21). Ultra-rare (popmax 0.0657%, afr); Associated with Jeune syndrome.

What condition is associated with DYNC2H1 p.Ala1245= (c.3735C>T)?

DYNC2H1 p.Ala1245= (c.3735C>T) is associated with Jeune syndrome, asphyxiating thoracic dystrophy 3 (ClinVar).

How common is DYNC2H1 p.Ala1245= (c.3735C>T) in the general population?

DYNC2H1 p.Ala1245= (c.3735C>T) is ultra-rare (popmax 0.0657%, afr) (gnomAD).

DYNC2H1 p.Ala1245=

c.3735C>T · rs377584612 · VCV302030

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0657%, afr)

Conditions

Jeune syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.23	GERP -2.5, phastCons 0.28
Overall
CADD	9.674	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0657% African / African-American · 49/74,544 alleles

Filtering AF 0.051% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0458%

Overall 0.0105% 169/1,607,076 alleles · ultra-rare exomes 135/1,455,268 · genomes 34/151,808 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0657%	1,521
South Asian	0.0616%	1,624
Admixed American	0.022%	4,544
Remaining individualsnot grpmax-eligible	0.00965%	10,364
European (non-Finnish)	0.00391%	25,591

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.Ala1245=
Coding: c.3735C>T
MANE Select: NM_001377
dbSNP: rs377584612
Type: single nucleotide variant
Location: chr11:103155492 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1245: 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

Also linked: asphyxiating thoracic dystrophy 3

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.12156+1G>A Pathogenic/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-ala1245 (accessed [today's date]).

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