Is DYNC2H1 p.Ser4194Phe (c.12581C>T) pathogenic?

DYNC2H1 p.Ser4194Phe (c.12581C>T) is classified Conflicting classifications of pathogenicity in DYNC2H1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-08-06). AlphaMissense: likely pathogenic (0.8416); Very rare (popmax 0.00535%, afr); Associated with asphyxiating thoracic dystrophy 3.

What condition is associated with DYNC2H1 p.Ser4194Phe (c.12581C>T)?

DYNC2H1 p.Ser4194Phe (c.12581C>T) is associated with asphyxiating thoracic dystrophy 3 (ClinVar).

How common is DYNC2H1 p.Ser4194Phe (c.12581C>T) in the general population?

DYNC2H1 p.Ser4194Phe (c.12581C>T) is very rare (popmax 0.00535%, afr) (gnomAD).

What do computational predictors say about DYNC2H1 p.Ser4194Phe (c.12581C>T)?

AlphaMissense predicts likely pathogenic (score 0.8416) — an in-silico prediction, not a clinical call.

DYNC2H1 p.Ser4194Phe

c.12581C>T · rs886042136 · VCV281351

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.8416 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00535%, afr)

Conditions

asphyxiating thoracic dystrophy 3

Computational evidence

Protein change
AlphaMissense	0.8416	likely pathogenic
REVEL	0.393	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 293 kb · p 0.28 · regional, not allelic
Overall
CADD	28.2	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 0.00535% African / African-American · 4/74,806 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.000435% 7/1,608,378 alleles · very rare exomes 5/1,456,332 · genomes 2/152,046 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00535%	18,702
Remaining individualsnot grpmax-eligible	0.00482%	20,759

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.Ser4194Phe
Coding: c.12581C>T
MANE Select: NM_001377
dbSNP: rs886042136
Type: single nucleotide variant
Location: chr11:103456289 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)

Full DYNC2H1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

asphyxiating thoracic dystrophy 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DYNC2H1 p.Ser4194= Likely benign ★ same residue
DYNC2H1 c.10042+2T>G Pathogenic/Likely pathogenic ★★ same condition
DYNC2H1 c.10462-2A>G Likely pathogenic ★★ same condition
DYNC2H1 c.10606-14A>G Pathogenic/Likely pathogenic ★★ same condition
DYNC2H1 c.12156+1G>A Pathogenic/Likely pathogenic ★★ same condition
DYNC2H1 c.12457-1G>C Likely pathogenic ★★ same condition
DYNC2H1 c.1662-2A>G Likely pathogenic ★★ same condition
DYNC2H1 c.2106+2T>C 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/dync2h1-p-ser4194phe (accessed [today's date]).

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