Is DYNC1H1 p.Ser28Trp (c.83C>G) pathogenic?

DYNC1H1 p.Ser28Trp (c.83C>G) is classified Uncertain significance in DYNC1H1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-09-15). AlphaMissense: likely benign (0.322); Very rare (popmax 0.0045%, eas); Associated with DYNC1H1-related disorder.

How common is DYNC1H1 p.Ser28Trp (c.83C>G) in the general population?

DYNC1H1 p.Ser28Trp (c.83C>G) is very rare (popmax 0.0045%, eas) (gnomAD).

What do computational predictors say about DYNC1H1 p.Ser28Trp (c.83C>G)?

AlphaMissense predicts likely benign (score 0.322) — an in-silico prediction, not a clinical call.

DYNC1H1 p.Ser28Trp

Q: What condition is associated with DYNC1H1 p.Ser28Trp (c.83C>G)?

DYNC1H1 p.Ser28Trp (c.83C>G) is associated with DYNC1H1-related disorder, autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures, Charcot-Marie-Tooth disease axonal type 2O (ClinVar).

c.83C>G · rs765882472 · VCV1184382

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.322 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0045%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

DYNC1H1-related disorder

Computational evidence

Protein change
AlphaMissense	0.322	likely benign
REVEL	0.122	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	GERP 0.88, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 225 bp · p 0.67 · regional, not allelic
Overall
CADD	25.3	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 0.0045% East Asian · 2/44,476 alleles

Filtering AF 0.00107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000375% 6/1,600,136 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0045%	22,238
African / African-American	0.00401%	24,921
Remaining individualsnot grpmax-eligible	0.00161%	61,930

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.Ser28Trp
Coding: c.83C>G
MANE Select: NM_001376
dbSNP: rs765882472
Type: single nucleotide variant
Location: chr14:101964774 (GRCh38)
Gene constraint: LOEUF 0.117 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 28: an α-helix

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

Disease context

Also linked: autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures Charcot-Marie-Tooth disease axonal type 2O cortical dysplasia, complex, with other brain malformations 13

Similar variants

DYNC1H1 p.Ser28Leu Likely benign ★★ same residue
DYNC1H1 c.4396-1G>C Likely pathogenic ★★ same condition
DYNC1H1 p.Ala4519Val Likely pathogenic ★★ same condition
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

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-ser28trp (accessed [today's date]).

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