Is DYNC2I1 p.Pro347Thr (c.1039C>A) pathogenic?

DYNC2I1 p.Pro347Thr (c.1039C>A) is classified Uncertain significance in DYNC2I1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-26). AlphaMissense: likely benign (0.0647); Very rare (popmax 0.00619%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DYNC2I1 p.Pro347Thr (c.1039C>A)?

DYNC2I1 p.Pro347Thr (c.1039C>A) is associated with Inborn genetic diseases (ClinVar).

How common is DYNC2I1 p.Pro347Thr (c.1039C>A) in the general population?

DYNC2I1 p.Pro347Thr (c.1039C>A) is very rare (popmax 0.00619%, nfe) (gnomAD).

What do computational predictors say about DYNC2I1 p.Pro347Thr (c.1039C>A)?

AlphaMissense predicts likely benign (score 0.0647) — an in-silico prediction, not a clinical call.

DYNC2I1 p.Pro347Thr

c.1039C>A · rs748753193 · VCV3086506

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0647 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00619%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0647	likely benign
REVEL	0.062	moderately benign-leaning
SaProt	LLR -5.87	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 1.1	GERP 0.96, phastCons 0.007
Regional constraint	o/e 0.98	unconstrained · MANE · 89 kb · p 0.52 · regional, not allelic
Overall
CADD	6.994	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 0.00619% European (non-Finnish) · 73/1,179,912 alleles

Filtering AF 0.00503% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00462%

Overall 0.00471% 76/1,613,920 alleles · very rare exomes 73/1,461,700 · genomes 3/152,220 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00619%	16,163
Remaining individualsnot grpmax-eligible	0.0048%	20,821

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.Pro347Thr
Coding: c.1039C>A
MANE Select: NM_018051
dbSNP: rs748753193
Type: single nucleotide variant
Location: chr7:158891313 (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 347: the 'disordered' region

Full DYNC2I1 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

Similar variants

DYNC2I1 p.Pro347Leu Likely benign ★★ same residue
DYNC2I1 p.Pro347= Likely benign ★ same residue
DYNC2I1 p.Ala157Val Uncertain significance ★★ ⚠ same condition
DYNC2I1 p.Ala822Thr Uncertain significance ★★ ⚠ same condition
DYNC2I1 p.Ala956Val Uncertain significance ★★ ⚠ same condition
DYNC2I1 p.Arg1038Trp Uncertain significance ★★ ⚠ same condition
DYNC2I1 p.Arg109Gln Uncertain significance ★★ ⚠ same condition
DYNC2I1 p.Arg149Cys 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-pro347thr (accessed [today's date]).

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