Is DYNC1H1 p.Ser1122Phe (c.3365C>T) pathogenic?

DYNC1H1 p.Ser1122Phe (c.3365C>T) is classified Conflicting classifications of pathogenicity in DYNC1H1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-04-26). AlphaMissense: likely pathogenic (0.7604); Absent from gnomAD v4.1; Associated with cortical dysplasia, complex, with other brain malformations 13.

How common is DYNC1H1 p.Ser1122Phe (c.3365C>T) in the general population?

DYNC1H1 p.Ser1122Phe (c.3365C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DYNC1H1 p.Ser1122Phe (c.3365C>T)?

AlphaMissense predicts likely pathogenic (score 0.7604) — an in-silico prediction, not a clinical call.

DYNC1H1 p.Ser1122Phe

Q: What condition is associated with DYNC1H1 p.Ser1122Phe (c.3365C>T)?

DYNC1H1 p.Ser1122Phe (c.3365C>T) is associated with cortical dysplasia, complex, with other brain malformations 13, Charcot-Marie-Tooth disease axonal type 2O (ClinVar).

c.3365C>T · rs1459382670 · VCV2572598

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7604 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

cortical dysplasia, complex, with other brain malformations 13

Computational evidence

Protein change
AlphaMissense	0.7604	likely pathogenic
REVEL	0.471	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 0.10	constrained · MANE · 215 bp · p 8.1e-07 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DYNC1H1
Protein: p.Ser1122Phe
Coding: c.3365C>T
MANE Select: NM_001376
dbSNP: rs1459382670
Type: single nucleotide variant
Location: chr14:101995017 (GRCh38)
Gene constraint: LOEUF 0.117 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 1122: an α-helix; the 'stem' region

Full DYNC1H1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cortical dysplasia, complex, with other brain malformations 13 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Charcot-Marie-Tooth disease axonal type 2O

Similar variants

DYNC1H1 p.Arg1567Gln Pathogenic/Likely pathogenic ★★ same condition
DYNC1H1 p.Arg1623Gln Pathogenic/Likely pathogenic ★★ same condition
DYNC1H1 p.Arg1623Trp Pathogenic ★★ same condition
DYNC1H1 p.Arg1962Cys Pathogenic ★★ same condition
DYNC1H1 p.Arg1962His Likely pathogenic ★★ same condition
DYNC1H1 p.Arg2332Cys Pathogenic/Likely pathogenic ★★ same condition
DYNC1H1 p.Arg2492Ter Likely pathogenic ★★ same condition
DYNC1H1 p.Arg251Ser Pathogenic/Likely 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/dync1h1-p-ser1122phe (accessed [today's date]).

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