Is DYNC1H1 p.Ala4551Val (c.13652C>T) pathogenic?

DYNC1H1 p.Ala4551Val (c.13652C>T) is classified Conflicting classifications of pathogenicity in DYNC1H1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-17). AlphaMissense: likely benign (0.079); Very rare (popmax 0.00178%, nfe); Associated with cortical dysplasia, complex, with other brain malformations 13.

What condition is associated with DYNC1H1 p.Ala4551Val (c.13652C>T)?

DYNC1H1 p.Ala4551Val (c.13652C>T) is associated with cortical dysplasia, complex, with other brain malformations 13, autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures, Charcot-Marie-Tooth disease axonal type 2O (ClinVar).

How common is DYNC1H1 p.Ala4551Val (c.13652C>T) in the general population?

DYNC1H1 p.Ala4551Val (c.13652C>T) is very rare (popmax 0.00178%, nfe) (gnomAD).

What do computational predictors say about DYNC1H1 p.Ala4551Val (c.13652C>T)?

AlphaMissense predicts likely benign (score 0.079) — an in-silico prediction, not a clinical call.

DYNC1H1 p.Ala4551Val

c.13652C>T · rs1181756021 · VCV952660

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.079 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00178%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

cortical dysplasia, complex, with other brain malformations 13

Computational evidence

Protein change
AlphaMissense	0.079	likely benign
REVEL	0.147	moderately 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 7.5	GERP 2, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 737 bp · p 0.0048 · regional, not allelic
Overall
CADD	19.95	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 0.00178% European (non-Finnish) · 21/1,180,040 alleles

Filtering AF 0.00114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000971%

Overall 0.0013% 21/1,613,782 alleles · very rare

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.Ala4551Val
Coding: c.13652C>T
MANE Select: NM_001376
dbSNP: rs1181756021
Type: single nucleotide variant
Location: chr14:102049850 (GRCh38)
Gene constraint: LOEUF 0.117 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)

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

Disease context

cortical dysplasia, complex, with other brain malformations 13 — 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

Similar variants

DYNC1H1 p.Ala4551Thr Conflicting classifications of pathogenicity ★ ⚠ 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-ala4551val (accessed [today's date]).

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