Is DYNC2H1 p.Leu3441Pro (c.10322T>C) pathogenic?

DYNC2H1 p.Leu3441Pro (c.10322T>C) is classified Pathogenic/Likely pathogenic in DYNC2H1 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-01-12). AlphaMissense: likely pathogenic (0.9945); Ultra-rare (popmax 0.0107%, nfe); Associated with asphyxiating thoracic dystrophy 3.

What condition is associated with DYNC2H1 p.Leu3441Pro (c.10322T>C)?

DYNC2H1 p.Leu3441Pro (c.10322T>C) is associated with asphyxiating thoracic dystrophy 3, short-rib thoracic dysplasia 6 with or without polydactyly, Jeune syndrome (ClinVar).

How common is DYNC2H1 p.Leu3441Pro (c.10322T>C) in the general population?

DYNC2H1 p.Leu3441Pro (c.10322T>C) is ultra-rare (popmax 0.0107%, nfe) (gnomAD).

What do computational predictors say about DYNC2H1 p.Leu3441Pro (c.10322T>C)?

AlphaMissense predicts likely pathogenic (score 0.9945) — an in-silico prediction, not a clinical call.

DYNC2H1 p.Leu3441Pro

c.10322T>C · rs771487311 · VCV369661

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.9945 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

asphyxiating thoracic dystrophy 3

Computational evidence

Protein change
AlphaMissense	0.9945	likely pathogenic ✓ concordant with ClinVar · top 1% in DYNC2H1
REVEL	0.824	moderately pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 293 kb · p 0.28 · regional, not allelic
Overall
CADD	26.1	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 0.0107% European (non-Finnish) · 123/1,146,786 alleles

Filtering AF 0.00918% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0086%

Overall 0.00852% 132/1,549,064 alleles · ultra-rare exomes 123/1,396,910 · genomes 9/152,154 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0107%	9,323
Remaining individualsnot grpmax-eligible	0.00666%	15,016
African / African-American	0.00549%	18,222
Ashkenazi Jewishnot grpmax-eligible	0.00351%	28,526

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.Leu3441Pro
Coding: c.10322T>C
MANE Select: NM_001377
dbSNP: rs771487311
Type: single nucleotide variant
Location: chr11:103255530 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 3441: an α-helix; the 'aaa 5' region

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

Disease context

asphyxiating thoracic dystrophy 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: short-rib thoracic dysplasia 6 with or without polydactyly Jeune syndrome

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-leu3441pro (accessed [today's date]).

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