Is DYNC2I2 p.Leu319= (c.957G>A) pathogenic?

DYNC2I2 p.Leu319= (c.957G>A) is classified Benign in DYNC2I2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-27). Common (popmax 6.32%, eas) — too common for a highly-penetrant pathogenic allele; Associated with short-rib thoracic dysplasia 11 with or without polydactyly.

What condition is associated with DYNC2I2 p.Leu319= (c.957G>A)?

DYNC2I2 p.Leu319= (c.957G>A) is associated with short-rib thoracic dysplasia 11 with or without polydactyly (ClinVar).

DYNC2I2 p.Leu319=

Q: How common is DYNC2I2 p.Leu319= (c.957G>A) in the general population?

DYNC2I2 p.Leu319= (c.957G>A) is common (popmax 6.32%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.957G>A · rs75450756 · VCV474851

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Common

common (popmax 6.32%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

short-rib thoracic dysplasia 11 with or without polydactyly

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.41	GERP -2.7, phastCons 0.99
Overall
CADD	7.674	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.32% East Asian · 2,836/44,852 alleles

Filtering AF 6.13% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.05%

Overall 0.487% 7,853/1,612,520 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	6.32%	16
Finnishnot grpmax-eligible	3.01%	33
Remaining individualsnot grpmax-eligible	0.649%	154
Admixed American	0.641%	156
Ashkenazi Jewishnot grpmax-eligible	0.585%	171
South Asian	0.44%	228
European (non-Finnish)	0.146%	687
Middle Eastern	0.0838%	1,194
African / African-American	0.0373%	2,680

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.Leu319=
Coding: c.957G>A
MANE Select: NM_052844
dbSNP: rs75450756
Type: single nucleotide variant
Location: chr9:128635116 (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

Similar variants

DYNC2I2 p.Leu319fs Pathogenic ★ 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-leu319 (accessed [today's date]).

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