Is DYNC2I1 p.Ser459Phe (c.1376C>T) pathogenic?

DYNC2I1 p.Ser459Phe (c.1376C>T) is classified Uncertain significance in DYNC2I1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-18). AlphaMissense: likely benign (0.1191); Ultra-rare (popmax 0.0132%, sas); Associated with Inborn genetic diseases.

What condition is associated with DYNC2I1 p.Ser459Phe (c.1376C>T)?

DYNC2I1 p.Ser459Phe (c.1376C>T) is associated with Inborn genetic diseases (ClinVar).

How common is DYNC2I1 p.Ser459Phe (c.1376C>T) in the general population?

DYNC2I1 p.Ser459Phe (c.1376C>T) is ultra-rare (popmax 0.0132%, sas) (gnomAD).

What do computational predictors say about DYNC2I1 p.Ser459Phe (c.1376C>T)?

AlphaMissense predicts likely benign (score 0.1191) — an in-silico prediction, not a clinical call.

DYNC2I1 p.Ser459Phe

c.1376C>T · rs368662058 · VCV3086510

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1191 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0132%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1191	likely benign
REVEL	0.064	moderately benign-leaning
SaProt	LLR -8.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.22	acceptor loss, 18 bp away · masked 0 · deltas
Pangolin	Δ0.24	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 4.7	GERP 0.89, phastCons 0.48
Regional constraint	o/e 0.98	unconstrained · MANE · 89 kb · p 0.52 · regional, not allelic
Overall
CADD	21.7	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 0.0132% South Asian · 12/91,024 alleles

Filtering AF 0.00751% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00593%

Overall 0.00403% 65/1,613,704 alleles · ultra-rare exomes 58/1,461,512 · genomes 7/152,192 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0132%	7,585
Remaining individualsnot grpmax-eligible	0.0064%	15,614
European (non-Finnish)	0.00407%	24,580
Admixed American	0.00167%	59,992

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.Ser459Phe
Coding: c.1376C>T
MANE Select: NM_018051
dbSNP: rs368662058
Type: single nucleotide variant
Location: chr7:158906007 (GRCh38)
Gene constraint: LOEUF 0.802 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 62.87 · 4 PDB

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.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
DYNC2I1 p.Arg162Leu Uncertain significance ★★ ⚠ same condition
DYNC2I1 p.Arg319Gly 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-ser459phe (accessed [today's date]).

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