Is DYNC2H1 p.Asp992Asn (c.2974G>A) pathogenic?

DYNC2H1 p.Asp992Asn (c.2974G>A) is classified Uncertain significance in DYNC2H1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-08-23). AlphaMissense: likely benign (0.0736); Ultra-rare (popmax 0.0682%, mid); Associated with asphyxiating thoracic dystrophy 3.

What condition is associated with DYNC2H1 p.Asp992Asn (c.2974G>A)?

DYNC2H1 p.Asp992Asn (c.2974G>A) is associated with asphyxiating thoracic dystrophy 3, Jeune syndrome, inherited retinal dystrophy (ClinVar).

How common is DYNC2H1 p.Asp992Asn (c.2974G>A) in the general population?

DYNC2H1 p.Asp992Asn (c.2974G>A) is ultra-rare (popmax 0.0682%, mid) (gnomAD).

What do computational predictors say about DYNC2H1 p.Asp992Asn (c.2974G>A)?

AlphaMissense predicts likely benign (score 0.0736) — an in-silico prediction, not a clinical call.

DYNC2H1 p.Asp992Asn

c.2974G>A · rs200222210 · VCV1015731

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0736 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0682%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

asphyxiating thoracic dystrophy 3

Computational evidence

Protein change
AlphaMissense	0.0736	likely benign
REVEL	0.069	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.9	GERP -0.014, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 61 kb · p 0.56 · regional, not allelic
Overall
CADD	19.22	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0682% Middle Eastern · 4/5,864 alleles

Filtering AF 0.0232% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.014%

Overall 0.00768% 123/1,602,158 alleles · ultra-rare exomes 115/1,454,076 · genomes 8/148,082 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0682%	1,466
Remaining individualsnot grpmax-eligible	0.00966%	10,347
European (non-Finnish)	0.00885%	11,305
South Asian	0.00786%	12,724
Ashkenazi Jewishnot grpmax-eligible	0.0034%	29,408
Admixed American	0.00169%	59,066

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.Asp992Asn
Coding: c.2974G>A
MANE Select: NM_001377
dbSNP: rs200222210
Type: single nucleotide variant
Location: chr11:103152163 (GRCh38)
Gene constraint: LOEUF 0.859 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Residue 992: the 'stem' region

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 inherited retinal dystrophy

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-asp992asn (accessed [today's date]).

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