Is DYNC2H1 p.Pro4137Arg (c.12410C>G) pathogenic?

DYNC2H1 p.Pro4137Arg (c.12410C>G) is classified Conflicting classifications of pathogenicity in DYNC2H1 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2025-10-06). AlphaMissense: likely pathogenic (0.9497); Very rare (popmax 0.00399%, nfe); Associated with DYNC2H1-related disorder.

What condition is associated with DYNC2H1 p.Pro4137Arg (c.12410C>G)?

DYNC2H1 p.Pro4137Arg (c.12410C>G) is associated with DYNC2H1-related disorder, asphyxiating thoracic dystrophy 3, Jeune syndrome (ClinVar).

How common is DYNC2H1 p.Pro4137Arg (c.12410C>G) in the general population?

DYNC2H1 p.Pro4137Arg (c.12410C>G) is very rare (popmax 0.00399%, nfe) (gnomAD).

What do computational predictors say about DYNC2H1 p.Pro4137Arg (c.12410C>G)?

AlphaMissense predicts likely pathogenic (score 0.9497) — an in-silico prediction, not a clinical call.

DYNC2H1 p.Pro4137Arg

c.12410C>G · rs761765709 · VCV198962

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.9497 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00399%, nfe)

Conditions

DYNC2H1-related disorder

Computational evidence

Protein change
AlphaMissense	0.9497	likely pathogenic · top 9% in DYNC2H1
REVEL	0.495	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.8, 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 0.00399% European (non-Finnish) · 47/1,179,082 alleles

Filtering AF 0.00307% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00275%

Overall 0.0031% 50/1,612,468 alleles · very rare exomes 46/1,460,450 · genomes 4/152,018 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00399%	25,087
African / African-American	0.00267%	37,403
Remaining individualsnot grpmax-eligible	0.0016%	62,386

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.Pro4137Arg
Coding: c.12410C>G
MANE Select: NM_001377
dbSNP: rs761765709
Type: single nucleotide variant
Location: chr11:103435986 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 4137: an α-helix

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

Disease context

Also linked: asphyxiating thoracic dystrophy 3 Jeune syndrome

Similar variants

DYNC2H1 p.Pro4137Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
DYNC2H1 p.Pro4137Ser Conflicting classifications of pathogenicity ★ 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-pro4137arg (accessed [today's date]).

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