Is DYNC1H1 p.Phe1018Ser (c.3053T>C) pathogenic?

DYNC1H1 p.Phe1018Ser (c.3053T>C) is classified Conflicting classifications of pathogenicity in DYNC1H1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-07-17). AlphaMissense: likely benign (0.2242); Very rare (popmax 0.000254%, nfe); Associated with cortical dysplasia, complex, with other brain malformations 13.

How common is DYNC1H1 p.Phe1018Ser (c.3053T>C) in the general population?

DYNC1H1 p.Phe1018Ser (c.3053T>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about DYNC1H1 p.Phe1018Ser (c.3053T>C)?

AlphaMissense predicts likely benign (score 0.2242) — an in-silico prediction, not a clinical call.

DYNC1H1 p.Phe1018Ser

Q: What condition is associated with DYNC1H1 p.Phe1018Ser (c.3053T>C)?

DYNC1H1 p.Phe1018Ser (c.3053T>C) is associated with cortical dysplasia, complex, with other brain malformations 13, Charcot-Marie-Tooth disease axonal type 2O (ClinVar).

c.3053T>C · rs1318726169 · VCV976360

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2242 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

cortical dysplasia, complex, with other brain malformations 13

Computational evidence

Protein change
AlphaMissense	0.2242	likely benign
REVEL	0.403	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 8,162 bp · p 7.9e-20 · regional, not allelic
Overall
CADD	22.7	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

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,040 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,104 alleles · very rare exomes 2/1,461,882 · genomes 1/152,222 · 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: DYNC1H1
Protein: p.Phe1018Ser
Coding: c.3053T>C
MANE Select: NM_001376
dbSNP: rs1318726169
Type: single nucleotide variant
Location: chr14:101994221 (GRCh38)
Gene constraint: LOEUF 0.117 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 1018: 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.Phe1018Tyr Uncertain significance ★ same residue
DYNC1H1 p.Phe1018Leu Likely benign ★ same residue
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

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-phe1018ser (accessed [today's date]).

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