Is DYNC1H1 p.Ala492Pro (c.1474G>C) pathogenic?

DYNC1H1 p.Ala492Pro (c.1474G>C) is classified Uncertain significance in DYNC1H1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-04). AlphaMissense: likely benign (0.0726); Absent from gnomAD v4.1; Associated with DYNC1H1-related disorder.

What condition is associated with DYNC1H1 p.Ala492Pro (c.1474G>C)?

DYNC1H1 p.Ala492Pro (c.1474G>C) is associated with DYNC1H1-related disorder (ClinVar).

How common is DYNC1H1 p.Ala492Pro (c.1474G>C) in the general population?

DYNC1H1 p.Ala492Pro (c.1474G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DYNC1H1 p.Ala492Pro (c.1474G>C)?

AlphaMissense predicts likely benign (score 0.0726) — an in-silico prediction, not a clinical call.

DYNC1H1 p.Ala492Pro

c.1474G>C · VCV4854850

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0726 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

DYNC1H1-related disorder

Computational evidence

Protein change
AlphaMissense	0.0726	likely benign
REVEL	0.063	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 9.9	GERP 1.3, phastCons 1
Regional constraint	o/e 0.43	unconstrained · MANE · 3,602 bp · p 2.9e-46 · regional, not allelic
Overall
CADD	21.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DYNC1H1
Protein: p.Ala492Pro
Coding: c.1474G>C
MANE Select: NM_001376
Type: single nucleotide variant
Location: chr14:101985699 (GRCh38)
Gene constraint: LOEUF 0.117 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 492: the 'stem' region; the 'interaction with dync1i2' region

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

Disease context

DYNC1H1-related disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DYNC1H1 p.Ala492Thr Uncertain significance ★★ ⚠ same residue
DYNC1H1 p.Ala492Val Uncertain significance ★ ⚠ same residue
DYNC1H1 c.4396-1G>C Likely pathogenic ★★ same condition
DYNC1H1 p.Ala4519Val Likely pathogenic ★★ same condition
DYNC1H1 p.Arg2332Cys Pathogenic/Likely pathogenic ★★ same condition
DYNC1H1 p.Arg598Cys Pathogenic/Likely pathogenic ★★ same condition
DYNC1H1 p.Asp338Gly Pathogenic/Likely pathogenic ★★ same condition
DYNC1H1 p.Val612Met 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-ala492pro (accessed [today's date]).

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