Is DYNC2I2 p.Val195Met (c.583G>A) pathogenic?

DYNC2I2 p.Val195Met (c.583G>A) is classified Uncertain significance in DYNC2I2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-29). AlphaMissense: ambiguous (0.3562); Ultra-rare (popmax 0.0121%, sas); Associated with short-rib thoracic dysplasia 11 with or without polydactyly.

What condition is associated with DYNC2I2 p.Val195Met (c.583G>A)?

DYNC2I2 p.Val195Met (c.583G>A) is associated with short-rib thoracic dysplasia 11 with or without polydactyly (ClinVar).

How common is DYNC2I2 p.Val195Met (c.583G>A) in the general population?

DYNC2I2 p.Val195Met (c.583G>A) is ultra-rare (popmax 0.0121%, sas) (gnomAD).

What do computational predictors say about DYNC2I2 p.Val195Met (c.583G>A)?

AlphaMissense predicts ambiguous (score 0.3562) — an in-silico prediction, not a clinical call.

DYNC2I2 p.Val195Met

c.583G>A · rs370632485 · VCV1681238

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3562 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

short-rib thoracic dysplasia 11 with or without polydactyly

Computational evidence

Protein change
AlphaMissense	0.3562	ambiguous
REVEL	0.274	benign-leaning
SaProt	LLR -11.87	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.8, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 23 kb · p 0.59 · regional, not allelic
Overall
CADD	25.1	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 0.0121% South Asian · 11/90,658 alleles

Filtering AF 0.00851% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00796%

Overall 0.00832% 134/1,610,246 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0121%	8,242
European (non-Finnish)	0.01%	9,992
Admixed American	0.00334%	29,899
Remaining individualsnot grpmax-eligible	0.00321%	31,191
African / African-American	0.00134%	74,894

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.Val195Met
Coding: c.583G>A
MANE Select: NM_052844
dbSNP: rs370632485
Type: single nucleotide variant
Location: chr9:128636401 (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 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
DYNC2I2 p.Ala369Val 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-val195met (accessed [today's date]).

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