Is DYNC1I2 p.Val389Ile (c.1165G>A) pathogenic?

DYNC1I2 p.Val389Ile (c.1165G>A) is classified Uncertain significance in DYNC1I2 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely benign (0.143); Ultra-rare (popmax 0.0845%, sas); Associated with neurodevelopmental disorder with microcephaly and structural brain anomalies.

What condition is associated with DYNC1I2 p.Val389Ile (c.1165G>A)?

DYNC1I2 p.Val389Ile (c.1165G>A) is associated with neurodevelopmental disorder with microcephaly and structural brain anomalies (ClinVar).

How common is DYNC1I2 p.Val389Ile (c.1165G>A) in the general population?

DYNC1I2 p.Val389Ile (c.1165G>A) is ultra-rare (popmax 0.0845%, sas) (gnomAD).

What do computational predictors say about DYNC1I2 p.Val389Ile (c.1165G>A)?

AlphaMissense predicts likely benign (score 0.143) — an in-silico prediction, not a clinical call.

DYNC1I2 p.Val389Ile

c.1165G>A · VCV4533376

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.143 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0845%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodevelopmental disorder with microcephaly and structural brain anomalies

Computational evidence

Protein change
AlphaMissense	0.143	likely benign
REVEL	0.277	benign-leaning
SaProt	LLR -9.05	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 12	GERP 2.8, phastCons 1
Regional constraint	o/e 0.10	constrained · MANE · 387 bp · p 3.9e-05 · regional, not allelic
Overall
CADD	27.7	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 0.0845% South Asian · 75/88,752 alleles

Filtering AF 0.069% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0635%

Overall 0.00618% 99/1,602,166 alleles · ultra-rare exomes 95/1,450,160 · genomes 4/152,006 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0845%	1,183
Middle Eastern	0.0202%	4,944
Remaining individualsnot grpmax-eligible	0.00809%	12,367
Admixed American	0.00173%	57,730
European (non-Finnish)	0.00145%	69,166

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: DYNC1I2
Protein: p.Val389Ile
Coding: c.1165G>A
MANE Select: NM_001378
Type: single nucleotide variant
Location: chr2:171728326 (GRCh38)
Gene constraint: LOEUF 0.84 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.03 · 30 PDB
Residue 389: a UniProt-annotated variant site (in nedmiba; loss-of-function variant; does not rescue neurodevelopmental defects in zebrafish morphants); a β-strand

Full DYNC1I2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neurodevelopmental disorder with microcephaly and structural brain anomalies — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DYNC1I2 c.871-1G>A Likely pathogenic ★ same condition
DYNC1I2 p.Gln290Ter Pathogenic ★ same condition
DYNC1I2 p.Tyr247Cys Pathogenic ★ same condition
DYNC1I2 c.1678-3T>C Uncertain significance ★ same condition
DYNC1I2 c.245-19T>G Uncertain significance ★ same condition
DYNC1I2 p.Pro516Thr Uncertain significance ★ ⚠ same condition
DYNC1I2 c.607+1G>A Pathogenic same condition
DYNC1I2 p.Arg133Gln Uncertain significance ★★ ⚠ same type

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/dync1i2-p-val389ile (accessed [today's date]).

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