Is DYNC2I1 p.Arg593Gln (c.1778G>A) pathogenic?

DYNC2I1 p.Arg593Gln (c.1778G>A) is classified Conflicting classifications of pathogenicity in DYNC2I1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-20). AlphaMissense: likely benign (0.0844); Rare (popmax 0.56%, afr); Associated with short-rib thoracic dysplasia 8 with or without polydactyly.

What condition is associated with DYNC2I1 p.Arg593Gln (c.1778G>A)?

DYNC2I1 p.Arg593Gln (c.1778G>A) is associated with short-rib thoracic dysplasia 8 with or without polydactyly (ClinVar).

How common is DYNC2I1 p.Arg593Gln (c.1778G>A) in the general population?

DYNC2I1 p.Arg593Gln (c.1778G>A) is rare (popmax 0.56%, afr) (gnomAD).

What do computational predictors say about DYNC2I1 p.Arg593Gln (c.1778G>A)?

AlphaMissense predicts likely benign (score 0.0844) — an in-silico prediction, not a clinical call.

DYNC2I1 p.Arg593Gln

c.1778G>A · rs58538724 · VCV766803

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0844 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.56%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

short-rib thoracic dysplasia 8 with or without polydactyly

Computational evidence

Protein change
AlphaMissense	0.0844	likely benign
REVEL	0.266	benign-leaning
SaProt	LLR -5.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.9	GERP 0.71, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 89 kb · p 0.52 · regional, not allelic
Overall
CADD	20.8	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 0.56% African / African-American · 420/74,950 alleles

Filtering AF 0.516% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.499%

Overall 0.0287% 462/1,610,640 alleles · rare exomes 224/1,458,482 · genomes 238/152,158 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.56%	178
Remaining individualsnot grpmax-eligible	0.0257%	3,898
Admixed American	0.0218%	4,586
South Asian	0.00553%	18,074
East Asian	0.00223%	44,826
European (non-Finnish)	0.000594%	168,325

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: DYNC2I1
Protein: p.Arg593Gln
Coding: c.1778G>A
MANE Select: NM_018051
dbSNP: rs58538724
Type: single nucleotide variant
Location: chr7:158914308 (GRCh38)
Gene constraint: LOEUF 0.802 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 62.87 · 4 PDB

Full DYNC2I1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

short-rib thoracic dysplasia 8 with or without polydactyly — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DYNC2I1 p.Arg593Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
DYNC2I1 p.Arg228Ter Pathogenic/Likely pathogenic ★★ same condition
DYNC2I1 p.Arg441Ter Pathogenic/Likely pathogenic ★★ same condition
DYNC2I1 p.Arg642Ter Pathogenic/Likely pathogenic ★★ same condition
DYNC2I1 p.Arg762Ter Pathogenic ★★ same condition
DYNC2I1 p.Ala157Val Uncertain significance ★★ ⚠ same condition
DYNC2I1 p.Ala609Val Uncertain significance ★★ ⚠ same condition
DYNC2I1 p.Ala800Thr 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/dync2i1-p-arg593gln (accessed [today's date]).

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