Is DYNC2I2 p.His416Tyr (c.1246C>T) pathogenic?

DYNC2I2 p.His416Tyr (c.1246C>T) is classified Uncertain significance in DYNC2I2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-01). AlphaMissense: likely benign (0.1085); Ultra-rare (popmax 0.0166%, mid); Associated with Inborn genetic diseases.

What condition is associated with DYNC2I2 p.His416Tyr (c.1246C>T)?

DYNC2I2 p.His416Tyr (c.1246C>T) is associated with Inborn genetic diseases, short-rib thoracic dysplasia 11 with or without polydactyly (ClinVar).

How common is DYNC2I2 p.His416Tyr (c.1246C>T) in the general population?

DYNC2I2 p.His416Tyr (c.1246C>T) is ultra-rare (popmax 0.0166%, mid) (gnomAD).

What do computational predictors say about DYNC2I2 p.His416Tyr (c.1246C>T)?

AlphaMissense predicts likely benign (score 0.1085) — an in-silico prediction, not a clinical call.

DYNC2I2 p.His416Tyr

c.1246C>T · rs371747861 · VCV1681189

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1085 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0166%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1085	likely benign
REVEL	0.16	moderately benign-leaning
SaProt	LLR -6.01	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.23	donor gain · deltas
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 23 kb · p 0.59 · regional, not allelic
Overall
CADD	20.8	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 0.0166% Middle Eastern · 1/6,012 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000682%

Overall 0.00206% 33/1,605,482 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0485%	2,064
Remaining individualsnot grpmax-eligible	0.0177%	5,644
Middle Easterngrpmax	0.0166%	6,012
Admixed American	0.00519%	19,251
European (non-Finnish)	0.00034%	294,220

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.His416Tyr
Coding: c.1246C>T
MANE Select: NM_052844
dbSNP: rs371747861
Type: single nucleotide variant
Location: chr9:128634352 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: short-rib thoracic dysplasia 11 with or without polydactyly

Similar variants

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
DYNC2I2 p.Ala219Thr Uncertain significance ★★ ⚠ same condition
DYNC2I2 p.Ala369Val 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-his416tyr (accessed [today's date]).

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