Is DYNC2H1 p.Met1817Ile (c.5451G>A) pathogenic?

DYNC2H1 p.Met1817Ile (c.5451G>A) is classified Uncertain significance in DYNC2H1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-12). AlphaMissense: likely pathogenic (0.9624); Very rare (popmax 0.00179%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DYNC2H1 p.Met1817Ile (c.5451G>A)?

DYNC2H1 p.Met1817Ile (c.5451G>A) is associated with Inborn genetic diseases (ClinVar).

How common is DYNC2H1 p.Met1817Ile (c.5451G>A) in the general population?

DYNC2H1 p.Met1817Ile (c.5451G>A) is very rare (popmax 0.00179%, nfe) (gnomAD).

What do computational predictors say about DYNC2H1 p.Met1817Ile (c.5451G>A)?

AlphaMissense predicts likely pathogenic (score 0.9624) — an in-silico prediction, not a clinical call.

DYNC2H1 p.Met1817Ile

c.5451G>A · VCV3506062

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9624 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00179%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9624	likely pathogenic · top 8% in DYNC2H1
REVEL	0.607	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 7,315 bp · p 0.64 · regional, not allelic
Overall
CADD	28.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00179% European (non-Finnish) · 21/1,174,354 alleles

Filtering AF 0.00115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000975%

Overall 0.00137% 22/1,602,304 alleles · very rare exomes 22/1,450,212 · genomes 0/152,092 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00179%	55,922
Remaining individualsnot grpmax-eligible	0.00162%	61,898

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.Met1817Ile
Coding: c.5451G>A
MANE Select: NM_001377
Type: single nucleotide variant
Location: chr11:103173198 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 1817: 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.Met1817Val Conflicting classifications of pathogenicity ★ same residue
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

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-met1817ile (accessed [today's date]).

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