Is DYNC2I2 p.Thr228Met (c.683C>T) pathogenic?

DYNC2I2 p.Thr228Met (c.683C>T) is classified Uncertain significance in DYNC2I2 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-01-06). AlphaMissense: likely benign (0.0772); Very rare (popmax 0.00232%, eas); Associated with short-rib thoracic dysplasia 11 with or without polydactyly.

How common is DYNC2I2 p.Thr228Met (c.683C>T) in the general population?

DYNC2I2 p.Thr228Met (c.683C>T) is very rare (popmax 0.00232%, eas) (gnomAD).

What do computational predictors say about DYNC2I2 p.Thr228Met (c.683C>T)?

AlphaMissense predicts likely benign (score 0.0772) — an in-silico prediction, not a clinical call.

DYNC2I2 p.Thr228Met

Q: What condition is associated with DYNC2I2 p.Thr228Met (c.683C>T)?

DYNC2I2 p.Thr228Met (c.683C>T) is associated with short-rib thoracic dysplasia 11 with or without polydactyly, inherited retinal dystrophy (ClinVar).

c.683C>T · rs771473147 · VCV2200169

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0772 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00232%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

short-rib thoracic dysplasia 11 with or without polydactyly

Computational evidence

Protein change
AlphaMissense	0.0772	likely benign
REVEL	0.234	benign-leaning
SaProt	LLR -10.64	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP -0.27, phastCons 0.013
Regional constraint	o/e 1.02	unconstrained · MANE · 23 kb · p 0.59 · regional, not allelic
Overall
CADD	15.17	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00232% East Asian · 1/43,082 alleles

Filtering AF 0.000185% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000122%

Overall 0.000443% 7/1,580,368 alleles · very rare exomes 7/1,428,002 · genomes 0/152,366 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00232%	43,082
European (non-Finnish)	0.000516%	193,956

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: DYNC2I2
Protein: p.Thr228Met
Coding: c.683C>T
MANE Select: NM_052844
dbSNP: rs771473147
Type: single nucleotide variant
Location: chr9:128636301 (GRCh38)
Gene constraint: LOEUF 1.036 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.66 · 4 PDB

Full DYNC2I2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

short-rib thoracic dysplasia 11 with or without polydactyly — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: inherited retinal dystrophy

Similar variants

DYNC2I2 p.Thr228= Likely benign ★ same residue
DYNC2I2 c.1372+1G>A Pathogenic/Likely pathogenic ★★ same condition
DYNC2I2 p.Arg121Ter Pathogenic ★★ same condition
DYNC2I2 p.Arg182Trp Pathogenic/Likely pathogenic ★★ ⚠ same condition
DYNC2I2 p.Arg447Trp Pathogenic/Likely pathogenic ★★ same condition
DYNC2I2 p.Ala131Val Uncertain significance ★★ ⚠ same condition
DYNC2I2 p.Ala13Gly Uncertain significance ★★ ⚠ same condition
DYNC2I2 p.Ala219Thr 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/dync2i2-p-thr228met (accessed [today's date]).

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