Is DYNC2H1 p.Pro4137Ser (c.12409C>T) pathogenic?

DYNC2H1 p.Pro4137Ser (c.12409C>T) is classified Conflicting classifications of pathogenicity in DYNC2H1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-06-12). AlphaMissense: ambiguous (0.5247); Very rare (popmax 0.00501%, amr); Associated with Jeune syndrome.

What condition is associated with DYNC2H1 p.Pro4137Ser (c.12409C>T)?

DYNC2H1 p.Pro4137Ser (c.12409C>T) is associated with Jeune syndrome (ClinVar).

How common is DYNC2H1 p.Pro4137Ser (c.12409C>T) in the general population?

DYNC2H1 p.Pro4137Ser (c.12409C>T) is very rare (popmax 0.00501%, amr) (gnomAD).

What do computational predictors say about DYNC2H1 p.Pro4137Ser (c.12409C>T)?

AlphaMissense predicts ambiguous (score 0.5247) — an in-silico prediction, not a clinical call.

DYNC2H1 p.Pro4137Ser

c.12409C>T · rs751823989 · VCV2720393

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5247 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00501%, amr)

Conditions

Jeune syndrome

Computational evidence

Protein change
AlphaMissense	0.5247	ambiguous
REVEL	0.259	benign-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 293 kb · p 0.28 · regional, not allelic
Overall
CADD	25.2	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 0.00501% Admixed American · 3/59,842 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000669%

Overall 0.000496% 8/1,612,634 alleles · very rare exomes 8/1,460,478 · genomes 0/152,156 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00501%	19,947
European (non-Finnish)	0.000424%	235,820

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.Pro4137Ser
Coding: c.12409C>T
MANE Select: NM_001377
dbSNP: rs751823989
Type: single nucleotide variant
Location: chr11:103435985 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 4137: an α-helix

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

Similar variants

DYNC2H1 p.Pro4137Arg Conflicting classifications of pathogenicity ★ same residue
DYNC2H1 p.Pro4137Leu Conflicting classifications of pathogenicity ★ ⚠ 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.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

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-pro4137ser (accessed [today's date]).

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