Is DYNC2I2 p.Glu41Asp (c.123G>C) pathogenic?

DYNC2I2 p.Glu41Asp (c.123G>C) is classified Uncertain significance in DYNC2I2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-17). AlphaMissense: likely benign (0.2072); Very rare (popmax 0.000266%, nfe); Associated with short-rib thoracic dysplasia 11 with or without polydactyly.

What condition is associated with DYNC2I2 p.Glu41Asp (c.123G>C)?

DYNC2I2 p.Glu41Asp (c.123G>C) is associated with short-rib thoracic dysplasia 11 with or without polydactyly (ClinVar).

How common is DYNC2I2 p.Glu41Asp (c.123G>C) in the general population?

DYNC2I2 p.Glu41Asp (c.123G>C) is very rare (popmax 0.000266%, nfe) (gnomAD).

What do computational predictors say about DYNC2I2 p.Glu41Asp (c.123G>C)?

AlphaMissense predicts likely benign (score 0.2072) — an in-silico prediction, not a clinical call.

DYNC2I2 p.Glu41Asp

c.123G>C · rs1449047694 · VCV2106921

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2072 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000266%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

short-rib thoracic dysplasia 11 with or without polydactyly

Computational evidence

Protein change
AlphaMissense	0.2072	likely benign
REVEL	0.324	indeterminate
SaProt	LLR -6.54	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP 2.3, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 23 kb · p 0.59 · regional, not allelic
Overall
CADD	22.9	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 0.000266% European (non-Finnish) · 3/1,129,570 alleles

Filtering AF 7.1e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2e-05%

Overall 0.000224% 3/1,341,486 alleles · very rare

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.Glu41Asp
Coding: c.123G>C
MANE Select: NM_052844
dbSNP: rs1449047694
Type: single nucleotide variant
Location: chr9:128656604 (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.Glu41Gln Uncertain significance ★ ⚠ 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-glu41asp (accessed [today's date]).

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