Is DYNC1H1 p.Val1504Ile (c.4510G>A) pathogenic?

DYNC1H1 p.Val1504Ile (c.4510G>A) is classified Conflicting classifications of pathogenicity in DYNC1H1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-08-11). AlphaMissense: likely benign (0.1054); Very rare (popmax 0.00246%, nfe); Associated with Inborn genetic diseases.

How common is DYNC1H1 p.Val1504Ile (c.4510G>A) in the general population?

DYNC1H1 p.Val1504Ile (c.4510G>A) is very rare (popmax 0.00246%, nfe) (gnomAD).

What do computational predictors say about DYNC1H1 p.Val1504Ile (c.4510G>A)?

AlphaMissense predicts likely benign (score 0.1054) — an in-silico prediction, not a clinical call.

DYNC1H1 p.Val1504Ile

Q: What condition is associated with DYNC1H1 p.Val1504Ile (c.4510G>A)?

DYNC1H1 p.Val1504Ile (c.4510G>A) is associated with Inborn genetic diseases, autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures, Charcot-Marie-Tooth disease axonal type 2O (ClinVar).

c.4510G>A · rs761695197 · VCV246361

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1054 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00246%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1054	likely benign
REVEL	0.2	benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 6,600 bp · p 8.5e-29 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00246% European (non-Finnish) · 29/1,180,044 alleles

Filtering AF 0.00172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00316% 51/1,614,084 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0676%	1,480
European (non-Finnish)grpmax	0.00246%	40,691
Admixed American	0.00167%	60,002
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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: DYNC1H1
Protein: p.Val1504Ile
Coding: c.4510G>A
MANE Select: NM_001376
dbSNP: rs761695197
Type: single nucleotide variant
Location: chr14:102001649 (GRCh38)
Gene constraint: LOEUF 0.117 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 1504: an α-helix; the 'stem' region

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: autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures Charcot-Marie-Tooth disease axonal type 2O cortical dysplasia, complex, with other brain malformations 13

Similar variants

DYNC1H1 p.Val1504= Likely benign ★ same residue
DYNC1H1 p.Arg1567Gln Pathogenic/Likely pathogenic ★★ same condition
DYNC1H1 p.Arg1623Gln Pathogenic/Likely pathogenic ★★ same condition
DYNC1H1 p.Arg1623Trp 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.Arg2492Ter 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/dync1h1-p-val1504ile (accessed [today's date]).

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