Is DYNC2I1 p.Arg495Trp (c.1483C>T) pathogenic?

DYNC2I1 p.Arg495Trp (c.1483C>T) is classified Uncertain significance in DYNC2I1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-20). AlphaMissense: ambiguous (0.4346); Very rare (popmax 0.00668%, afr); Associated with short-rib thoracic dysplasia 8 with or without polydactyly.

What condition is associated with DYNC2I1 p.Arg495Trp (c.1483C>T)?

DYNC2I1 p.Arg495Trp (c.1483C>T) is associated with short-rib thoracic dysplasia 8 with or without polydactyly (ClinVar).

How common is DYNC2I1 p.Arg495Trp (c.1483C>T) in the general population?

DYNC2I1 p.Arg495Trp (c.1483C>T) is very rare (popmax 0.00668%, afr) (gnomAD).

What do computational predictors say about DYNC2I1 p.Arg495Trp (c.1483C>T)?

AlphaMissense predicts ambiguous (score 0.4346) — an in-silico prediction, not a clinical call.

DYNC2I1 p.Arg495Trp

c.1483C>T · rs771932685 · VCV2165686

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4346 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

short-rib thoracic dysplasia 8 with or without polydactyly

Computational evidence

Protein change
AlphaMissense	0.4346	ambiguous
REVEL	0.788	moderately pathogenic-leaning
SaProt	LLR -11.16	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	Δ0.25	acceptor loss, 22 bp away · masked 0 · deltas
Pangolin	Δ0.21	loss · gain 0.03 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5.7	GERP 1.1, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 89 kb · p 0.52 · regional, not allelic
Overall
CADD	28.8	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 0.00668% African / African-American · 5/74,900 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00162%

Overall 0.000496% 8/1,613,326 alleles · very rare exomes 4/1,461,198 · genomes 4/152,128 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00668%	14,980
East Asian	0.00223%	44,862
European (non-Finnish)	0.00017%	589,870

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.Arg495Trp
Coding: c.1483C>T
MANE Select: NM_018051
dbSNP: rs771932685
Type: single nucleotide variant
Location: chr7:158911572 (GRCh38)
Gene constraint: LOEUF 0.802 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 62.87 · 4 PDB
Residue 495: the 'binding to the dynlt2b-dynlt1/dynlt3 dimer' region

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.Arg495Gln Uncertain significance ★ ⚠ same residue
DYNC2I1 p.Arg495Pro Uncertain significance ★ ⚠ 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

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-arg495trp (accessed [today's date]).

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