Is DYNC2I2 p.Ala535Val (c.1604C>T) pathogenic?

DYNC2I2 p.Ala535Val (c.1604C>T) is classified Uncertain significance in DYNC2I2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-18). AlphaMissense: likely benign (0.1147); Ultra-rare (popmax 0.0174%, mid); Associated with short-rib thoracic dysplasia 11 with or without polydactyly.

What condition is associated with DYNC2I2 p.Ala535Val (c.1604C>T)?

DYNC2I2 p.Ala535Val (c.1604C>T) is associated with short-rib thoracic dysplasia 11 with or without polydactyly (ClinVar).

How common is DYNC2I2 p.Ala535Val (c.1604C>T) in the general population?

DYNC2I2 p.Ala535Val (c.1604C>T) is ultra-rare (popmax 0.0174%, mid) (gnomAD).

What do computational predictors say about DYNC2I2 p.Ala535Val (c.1604C>T)?

AlphaMissense predicts likely benign (score 0.1147) — an in-silico prediction, not a clinical call.

DYNC2I2 p.Ala535Val

c.1604C>T · rs758735687 · VCV1681162

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1147 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0174%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

short-rib thoracic dysplasia 11 with or without polydactyly

Computational evidence

Protein change
AlphaMissense	0.1147	likely benign
REVEL	0.129	moderately benign-leaning
SaProt	LLR -7.00	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.7, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 23 kb · p 0.59 · regional, not allelic
Overall
CADD	24.1	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

Grpmax group 0.0174% Middle Eastern · 1/5,754 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.00124% 20/1,612,648 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0174%	5,754
South Asian	0.00659%	15,177
East Asian	0.00445%	22,447
Admixed American	0.00333%	30,007
African / African-American	0.00267%	37,461
European (non-Finnish)	0.000593%	168,570

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: DYNC2I2
Protein: p.Ala535Val
Coding: c.1604C>T
MANE Select: NM_052844
dbSNP: rs758735687
Type: single nucleotide variant
Location: chr9:128633751 (GRCh38)
Gene constraint: LOEUF 1.036 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.66 · 4 PDB

Full DYNC2I2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

short-rib thoracic dysplasia 11 with or without polydactyly — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DYNC2I2 p.Ala535= Likely benign ★★ same residue
DYNC2I2 p.Ala535Glu Uncertain significance ★ ⚠ same residue
DYNC2I2 c.1372+1G>A Pathogenic/Likely pathogenic ★★ same condition
DYNC2I2 p.Arg121Ter Pathogenic ★★ same condition
DYNC2I2 p.Arg182Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
DYNC2I2 p.Arg447Trp Pathogenic/Likely pathogenic ★★ same condition
DYNC2I2 p.Ala131Val Uncertain significance ★★ ⚠ same condition
DYNC2I2 p.Ala13Gly 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/dync2i2-p-ala535val (accessed [today's date]).

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