Is DYNC1I2 p.Pro516Thr (c.1546C>A) pathogenic?

DYNC1I2 p.Pro516Thr (c.1546C>A) is classified Uncertain significance in DYNC1I2 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-02-19). AlphaMissense: likely pathogenic (0.8041); Very rare (popmax 0.00936%, afr); Associated with neurodevelopmental disorder with microcephaly and structural brain anomalies.

What condition is associated with DYNC1I2 p.Pro516Thr (c.1546C>A)?

DYNC1I2 p.Pro516Thr (c.1546C>A) is associated with neurodevelopmental disorder with microcephaly and structural brain anomalies (ClinVar).

How common is DYNC1I2 p.Pro516Thr (c.1546C>A) in the general population?

DYNC1I2 p.Pro516Thr (c.1546C>A) is very rare (popmax 0.00936%, afr) (gnomAD).

What do computational predictors say about DYNC1I2 p.Pro516Thr (c.1546C>A)?

AlphaMissense predicts likely pathogenic (score 0.8041) — an in-silico prediction, not a clinical call.

DYNC1I2 p.Pro516Thr

c.1546C>A · rs767705533 · VCV1029274

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8041 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00936%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neurodevelopmental disorder with microcephaly and structural brain anomalies

Computational evidence

Protein change
AlphaMissense	0.8041	likely pathogenic
REVEL	0.715	pathogenic-leaning
SaProt	LLR -15.02	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.9	GERP 1.2, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 20 kb · p 8.7e-11 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00936% African / African-American · 7/74,756 alleles

Filtering AF 0.00438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.000435% 7/1,609,450 alleles · very rare exomes 6/1,457,390 · genomes 1/152,060 · joint denominator

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.Pro516Thr
Coding: c.1546C>A
MANE Select: NM_001378
dbSNP: rs767705533
Type: single nucleotide variant
Location: chr2:171744058 (GRCh38)
Gene constraint: LOEUF 0.84 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.03 · 30 PDB
Residue 516: a UniProt-annotated variant site (in nedmiba; loss-of-function variant; does not rescue neurodevelopmental defects in zebrafish morphants); a UniProt-annotated variant site (in nedmiba; likely benign; can rescue neurodevelopmental defects in zebrafish morphants)

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 p.Pro516Ala Likely benign same residue
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.Val389Ile Uncertain significance ★ ⚠ same condition
DYNC1I2 c.607+1G>A Pathogenic 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/dync1i2-p-pro516thr (accessed [today's date]).

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