Is DYNC2H1 p.Pro1820Ser (c.5458C>T) pathogenic?

DYNC2H1 p.Pro1820Ser (c.5458C>T) is classified Uncertain significance in DYNC2H1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-18). AlphaMissense: likely pathogenic (0.8005); Ultra-rare (popmax 0.0171%, amr); Associated with Inborn genetic diseases.

What condition is associated with DYNC2H1 p.Pro1820Ser (c.5458C>T)?

DYNC2H1 p.Pro1820Ser (c.5458C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DYNC2H1 p.Pro1820Ser (c.5458C>T) in the general population?

DYNC2H1 p.Pro1820Ser (c.5458C>T) is ultra-rare (popmax 0.0171%, amr) (gnomAD).

What do computational predictors say about DYNC2H1 p.Pro1820Ser (c.5458C>T)?

AlphaMissense predicts likely pathogenic (score 0.8005) — an in-silico prediction, not a clinical call.

DYNC2H1 p.Pro1820Ser

c.5458C>T · rs1332581015 · VCV2349857

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8005 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0171%, amr)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8005	likely pathogenic
REVEL	0.687	pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 7,315 bp · p 0.64 · regional, not allelic
Overall
CADD	27.3	PHRED · no single calibrated threshold — expert panels disagree

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

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0171% Admixed American · 10/58,574 alleles

Filtering AF 0.0092% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00696%

Overall 0.000687% 11/1,602,272 alleles · ultra-rare exomes 7/1,450,338 · genomes 4/151,934 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0171%	5,857
European (non-Finnish)	8.52e-05%	1,174,386

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.Pro1820Ser
Coding: c.5458C>T
MANE Select: NM_001377
dbSNP: rs1332581015
Type: single nucleotide variant
Location: chr11:103173205 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1820: the 'aaa 1' region

Full DYNC2H1 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

Similar variants

DYNC2H1 p.Ala1794Ser Uncertain significance ★★ same condition
DYNC2H1 p.Ala1941Pro Uncertain significance ★★ same condition
DYNC2H1 p.Ala2961Val Uncertain significance ★★ ⚠ same condition
DYNC2H1 p.Ala3172Ser Uncertain significance ★★ same condition
DYNC2H1 p.Ala4003Gly Uncertain significance ★★ ⚠ same condition
DYNC2H1 p.Arg1043Cys Uncertain significance ★★ ⚠ same condition
DYNC2H1 p.Arg1153Gln Uncertain significance ★★ same condition
DYNC2H1 p.Arg1253Gln Uncertain significance ★★ 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-pro1820ser (accessed [today's date]).

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