Is DYNC1H1 p.Arg223Cys (c.667C>T) pathogenic?

DYNC1H1 p.Arg223Cys (c.667C>T) is classified Conflicting classifications of pathogenicity in DYNC1H1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-10-20). AlphaMissense: likely benign (0.1429); Very rare (popmax 0.00659%, sas); Associated with Inborn genetic diseases.

What condition is associated with DYNC1H1 p.Arg223Cys (c.667C>T)?

DYNC1H1 p.Arg223Cys (c.667C>T) is associated with Inborn genetic diseases, Charcot-Marie-Tooth disease axonal type 2O (ClinVar).

How common is DYNC1H1 p.Arg223Cys (c.667C>T) in the general population?

DYNC1H1 p.Arg223Cys (c.667C>T) is very rare (popmax 0.00659%, sas) (gnomAD).

What do computational predictors say about DYNC1H1 p.Arg223Cys (c.667C>T)?

AlphaMissense predicts likely benign (score 0.1429) — an in-silico prediction, not a clinical call.

DYNC1H1 p.Arg223Cys

c.667C>T · rs757819428 · VCV848239

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1429 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1429	likely benign
REVEL	0.193	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 7.6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.51	unconstrained · MANE · 16 kb · p 5.6e-17 · regional, not allelic
Overall
CADD	27.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00659% South Asian · 6/91,086 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.000496% 8/1,613,978 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00659%	15,181
Admixed American	0.00167%	59,984
African / African-American	0.00134%	74,874

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.Arg223Cys
Coding: c.667C>T
MANE Select: NM_001376
dbSNP: rs757819428
Type: single nucleotide variant
Location: chr14:101979867 (GRCh38)
Gene constraint: LOEUF 0.117 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Residue 223: the 'stem' region

Full DYNC1H1 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

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

Similar variants

DYNC1H1 p.Arg223His Likely benign ★★ same residue
DYNC1H1 p.Arg1567Gln Pathogenic/Likely pathogenic ★★ same condition
DYNC1H1 p.Arg1623Gln Pathogenic/Likely 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.Arg251Ser Pathogenic/Likely pathogenic ★★ same condition
DYNC1H1 p.Arg264Leu 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-arg223cys (accessed [today's date]).

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