Is DYNC2H1 p.Met3755Val (c.11263A>G) pathogenic?

DYNC2H1 p.Met3755Val (c.11263A>G) is classified Conflicting classifications of pathogenicity in DYNC2H1 (ClinVar, Conflicting submitters, 17 submitters; last evaluated 2026-01-28). AlphaMissense: ambiguous (0.4865); Rare (popmax 0.333%, afr); Associated with Jeune syndrome.

What condition is associated with DYNC2H1 p.Met3755Val (c.11263A>G)?

DYNC2H1 p.Met3755Val (c.11263A>G) is associated with Jeune syndrome, retinal disorder, asphyxiating thoracic dystrophy 3 (ClinVar).

How common is DYNC2H1 p.Met3755Val (c.11263A>G) in the general population?

DYNC2H1 p.Met3755Val (c.11263A>G) is rare (popmax 0.333%, afr) (gnomAD).

What do computational predictors say about DYNC2H1 p.Met3755Val (c.11263A>G)?

AlphaMissense predicts ambiguous (score 0.4865) — an in-silico prediction, not a clinical call.

DYNC2H1 p.Met3755Val

c.11263A>G · rs137853026 · VCV6501

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 17 submitters

AlphaMissense

ambiguous

0.4865 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.333%, afr)

Conditions

Jeune syndrome

Computational evidence

Protein change
AlphaMissense	0.4865	ambiguous
REVEL	0.503	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 293 kb · p 0.28 · regional, not allelic
Overall
CADD	24.5	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 0.333% African / African-American · 249/74,878 alleles

Filtering AF 0.299% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.285%

Overall 0.0234% 376/1,609,680 alleles · rare exomes 222/1,457,464 · genomes 154/152,216 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.333%	301
Middle Eastern	0.116%	862
Remaining individualsnot grpmax-eligible	0.0321%	3,114
Admixed American	0.0318%	3,143
Ashkenazi Jewishnot grpmax-eligible	0.0136%	7,363
South Asian	0.00775%	12,901
European (non-Finnish)	0.00594%	16,822

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.Met3755Val
Coding: c.11263A>G
MANE Select: NM_001377
dbSNP: rs137853026
Type: single nucleotide variant
Location: chr11:103304601 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 3755: the 'aaa 6' region

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

Disease context

Jeune syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: retinal disorder asphyxiating thoracic dystrophy 3

Similar variants

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.10695+1G>A Likely pathogenic ★★ same condition
DYNC2H1 c.10813-2A>G Likely pathogenic ★★ same condition
DYNC2H1 c.11493+2T>A Likely pathogenic ★★ same condition
DYNC2H1 c.11650-1G>A Pathogenic/Likely pathogenic ★★ same condition
DYNC2H1 c.12156+1G>A 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/dync2h1-p-met3755val (accessed [today's date]).

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