Is DYNC2I1 p.Pro923Ser (c.2767C>T) pathogenic?

DYNC2I1 p.Pro923Ser (c.2767C>T) is classified Uncertain significance in DYNC2I1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-11). AlphaMissense: likely benign (0.1274); Ultra-rare (popmax 0.0105%, nfe); Associated with short-rib thoracic dysplasia 8 with or without polydactyly.

What condition is associated with DYNC2I1 p.Pro923Ser (c.2767C>T)?

DYNC2I1 p.Pro923Ser (c.2767C>T) is associated with short-rib thoracic dysplasia 8 with or without polydactyly (ClinVar).

How common is DYNC2I1 p.Pro923Ser (c.2767C>T) in the general population?

DYNC2I1 p.Pro923Ser (c.2767C>T) is ultra-rare (popmax 0.0105%, nfe) (gnomAD).

What do computational predictors say about DYNC2I1 p.Pro923Ser (c.2767C>T)?

AlphaMissense predicts likely benign (score 0.1274) — an in-silico prediction, not a clinical call.

DYNC2I1 p.Pro923Ser

c.2767C>T · rs770977639 · VCV1680722

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1274 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0105%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

short-rib thoracic dysplasia 8 with or without polydactyly

Computational evidence

Protein change
AlphaMissense	0.1274	likely benign
REVEL	0.052	moderately benign-leaning
SaProt	LLR -8.10	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.2	GERP 0.4, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 89 kb · p 0.52 · regional, not allelic
Overall
CADD	22.2	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0105% European (non-Finnish) · 120/1,147,452 alleles

Filtering AF 0.00892% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00835%

Overall 0.00786% 122/1,552,012 alleles · ultra-rare exomes 116/1,399,892 · genomes 6/152,120 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0105%	9,562
Remaining individualsnot grpmax-eligible	0.00332%	30,111

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: DYNC2I1
Protein: p.Pro923Ser
Coding: c.2767C>T
MANE Select: NM_018051
dbSNP: rs770977639
Type: single nucleotide variant
Location: chr7:158934538 (GRCh38)
Gene constraint: LOEUF 0.802 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 62.87 · 4 PDB
Residue 923: a UniProt-annotated variant site (in srtd8; reduces interaction with ift proteins); a UniProt-annotated variant site (in srtd8)

Full DYNC2I1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

short-rib thoracic dysplasia 8 with or without polydactyly — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DYNC2I1 p.Pro923Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
DYNC2I1 p.Arg228Ter Pathogenic/Likely pathogenic ★★ same condition
DYNC2I1 p.Arg441Ter Pathogenic/Likely pathogenic ★★ same condition
DYNC2I1 p.Arg642Ter Pathogenic/Likely pathogenic ★★ same condition
DYNC2I1 p.Arg762Ter Pathogenic ★★ same condition
DYNC2I1 p.Ala157Val Uncertain significance ★★ ⚠ same condition
DYNC2I1 p.Ala609Val Uncertain significance ★★ ⚠ same condition
DYNC2I1 p.Ala800Thr Uncertain significance ★★ ⚠ 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/dync2i1-p-pro923ser (accessed [today's date]).

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