Is DYNC2H1 p.Phe209Ile (c.625T>A) pathogenic?

DYNC2H1 p.Phe209Ile (c.625T>A) is classified Likely pathogenic in DYNC2H1 (ClinVar, Single submitter, 3 submitters; last evaluated 2024-05-31). AlphaMissense: likely benign (0.2926); Very rare (popmax 0.00793%, nfe); Associated with asphyxiating thoracic dystrophy 3.

What condition is associated with DYNC2H1 p.Phe209Ile (c.625T>A)?

DYNC2H1 p.Phe209Ile (c.625T>A) is associated with asphyxiating thoracic dystrophy 3, Jeune syndrome (ClinVar).

How common is DYNC2H1 p.Phe209Ile (c.625T>A) in the general population?

DYNC2H1 p.Phe209Ile (c.625T>A) is very rare (popmax 0.00793%, nfe) (gnomAD).

What do computational predictors say about DYNC2H1 p.Phe209Ile (c.625T>A)?

AlphaMissense predicts likely benign (score 0.2926) — an in-silico prediction, not a clinical call.

DYNC2H1 p.Phe209Ile

c.625T>A · rs771511132 · VCV446586

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2926 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00793%, nfe)

Conditions

asphyxiating thoracic dystrophy 3

Computational evidence

Protein change
AlphaMissense	0.2926	likely benign ⚠ discordant with ClinVar
REVEL	0.303	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.1, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 61 kb · p 0.56 · regional, not allelic
Overall
CADD	24.1	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 0.00793% European (non-Finnish) · 92/1,160,030 alleles

Filtering AF 0.00659% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00611%

Overall 0.0063% 99/1,570,464 alleles · very rare exomes 92/1,418,650 · genomes 7/151,814 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00991%	10,088
European (non-Finnish)grpmax	0.00793%	12,609
African / African-American	0.00137%	73,228

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe209Ile
Coding: c.625T>A
MANE Select: NM_001377
dbSNP: rs771511132
Type: single nucleotide variant
Location: chr11:103116573 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 209: the 'stem' region; a UniProt-annotated variant site (in srtd3)

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

Also linked: Jeune syndrome

Similar variants

DYNC2H1 p.Phe209fs Likely pathogenic ★ 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
DYNC2H1 c.11650-1G>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-phe209ile (accessed [today's date]).

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