Is DYNC1H1 p.Pro4198= (c.12594A>T) pathogenic?

DYNC1H1 p.Pro4198= (c.12594A>T) is classified Benign/Likely benign in DYNC1H1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-16). Ultra-rare (popmax 0.0134%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DYNC1H1 p.Pro4198= (c.12594A>T)?

DYNC1H1 p.Pro4198= (c.12594A>T) is associated with Inborn genetic diseases, Charcot-Marie-Tooth disease axonal type 2O, Charcot-Marie-Tooth disease (ClinVar).

How common is DYNC1H1 p.Pro4198= (c.12594A>T) in the general population?

DYNC1H1 p.Pro4198= (c.12594A>T) is ultra-rare (popmax 0.0134%, nfe) (gnomAD).

DYNC1H1 p.Pro4198=

c.12594A>T · rs143936619 · VCV514761

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4	GERP -4.6
Overall
CADD	1.63	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0134% European (non-Finnish) · 158/1,180,048 alleles

Filtering AF 0.0116% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.011%

Overall 0.0102% 164/1,614,072 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0134%	7,469
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
Remaining individualsnot grpmax-eligible	0.0032%	31,243
African / African-American	0.00267%	37,475
East Asian	0.00223%	44,880

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: DYNC1H1
Protein: p.Pro4198=
Coding: c.12594A>T
MANE Select: NM_001376
dbSNP: rs143936619
Type: single nucleotide variant
Location: chr14:102043955 (GRCh38)
Gene constraint: LOEUF 0.117 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 4198: the 'aaa 6' region; a turn

Full DYNC1H1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Charcot-Marie-Tooth disease axonal type 2O Charcot-Marie-Tooth disease

Similar variants

DYNC1H1 p.Pro4198Gln Uncertain significance ★ same residue
DYNC1H1 p.Arg1567Gln Pathogenic/Likely pathogenic ★★ same condition
DYNC1H1 p.Arg1623Gln Pathogenic/Likely pathogenic ★★ same condition
DYNC1H1 p.Arg1962Cys Pathogenic ★★ same condition
DYNC1H1 p.Arg1962His Likely pathogenic ★★ same condition
DYNC1H1 p.Arg2332Cys Pathogenic/Likely pathogenic ★★ same condition
DYNC1H1 p.Arg251Ser Pathogenic/Likely pathogenic ★★ same condition
DYNC1H1 p.Arg264Leu 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/dync1h1-p-pro4198 (accessed [today's date]).

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