Is DYNC2H1 p.Trp665Arg (c.1993T>A) pathogenic?

DYNC2H1 p.Trp665Arg (c.1993T>A) is classified Uncertain significance in DYNC2H1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-27). AlphaMissense: likely pathogenic (0.9985); Very rare (popmax 0.00401%, afr); Associated with Inborn genetic diseases.

What condition is associated with DYNC2H1 p.Trp665Arg (c.1993T>A)?

DYNC2H1 p.Trp665Arg (c.1993T>A) is associated with Inborn genetic diseases (ClinVar).

How common is DYNC2H1 p.Trp665Arg (c.1993T>A) in the general population?

DYNC2H1 p.Trp665Arg (c.1993T>A) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about DYNC2H1 p.Trp665Arg (c.1993T>A)?

AlphaMissense predicts likely pathogenic (score 0.9985) — an in-silico prediction, not a clinical call.

DYNC2H1 p.Trp665Arg

c.1993T>A · VCV3843045

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9985 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9985	likely pathogenic · top 1% in DYNC2H1
REVEL	0.92	moderately pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	Δ0.35	acceptor loss, 39 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 7.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 61 kb · p 0.56 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00401% African / African-American · 3/74,728 alleles

Filtering AF 0.00107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000496%

Overall 0.000248% 4/1,610,780 alleles · very rare exomes 0/1,458,676 · genomes 4/152,104 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,909
Admixed American	0.00168%	59,434

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: DYNC2H1
Protein: p.Trp665Arg
Coding: c.1993T>A
MANE Select: NM_001377
Type: single nucleotide variant
Location: chr11:103133594 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 665: the 'stem' region

Full DYNC2H1 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

DYNC2H1 p.Ala1794Ser Uncertain significance ★★ same condition
DYNC2H1 p.Ala1941Pro Uncertain significance ★★ same condition
DYNC2H1 p.Ala2961Val Uncertain significance ★★ ⚠ same condition
DYNC2H1 p.Ala3172Ser Uncertain significance ★★ same condition
DYNC2H1 p.Ala4003Gly Uncertain significance ★★ ⚠ same condition
DYNC2H1 p.Arg1043Cys Uncertain significance ★★ ⚠ same condition
DYNC2H1 p.Arg1153Gln Uncertain significance ★★ same condition
DYNC2H1 p.Arg1253Gln 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/dync2h1-p-trp665arg (accessed [today's date]).

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