Is DYNC2LI1 p.Leu6Phe (c.16C>T) pathogenic?

DYNC2LI1 p.Leu6Phe (c.16C>T) is classified Likely benign in DYNC2LI1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-01). AlphaMissense: ambiguous (0.4802); Rare (popmax 0.784%, afr); Associated with short-rib thoracic dysplasia 15 with polydactyly.

What condition is associated with DYNC2LI1 p.Leu6Phe (c.16C>T)?

DYNC2LI1 p.Leu6Phe (c.16C>T) is associated with short-rib thoracic dysplasia 15 with polydactyly (ClinVar).

How common is DYNC2LI1 p.Leu6Phe (c.16C>T) in the general population?

DYNC2LI1 p.Leu6Phe (c.16C>T) is rare (popmax 0.784%, afr) (gnomAD).

What do computational predictors say about DYNC2LI1 p.Leu6Phe (c.16C>T)?

AlphaMissense predicts ambiguous (score 0.4802) — an in-silico prediction, not a clinical call.

DYNC2LI1 p.Leu6Phe

c.16C>T · rs146698690 · VCV719316

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4802 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.784%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

short-rib thoracic dysplasia 15 with polydactyly

Computational evidence

Protein change
AlphaMissense	0.4802	ambiguous
REVEL	0.289	benign-leaning
SaProt	LLR -10.79	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.9	GERP 2, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 36 kb · p 0.00038 · regional, not allelic
Overall
CADD	24.7	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 0.784% African / African-American · 572/72,962 alleles

Filtering AF 0.731% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.71%

Overall 0.0419% 658/1,572,062 alleles · rare exomes 282/1,419,902 · genomes 376/152,160 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.784%	128
Admixed American	0.0553%	1,807
Remaining individualsnot grpmax-eligible	0.0529%	1,891
Ashkenazi Jewishnot grpmax-eligible	0.0417%	2,396
South Asian	0.00118%	85,036
European (non-Finnish)	0.000865%	115,596

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: DYNC2LI1
Protein: p.Leu6Phe
Coding: c.16C>T
MANE Select: NM_016008
dbSNP: rs146698690
Type: single nucleotide variant
Location: chr2:43776789 (GRCh38)
Gene constraint: LOEUF 1.028 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.49 · 3 PDB

Full DYNC2LI1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

short-rib thoracic dysplasia 15 with polydactyly — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DYNC2LI1 p.Leu117Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
DYNC2LI1 p.Trp124Ter Pathogenic/Likely pathogenic ★★ same condition
DYNC2LI1 p.Phe33Ser Benign ★★ same condition
DYNC2LI1 c.993+1G>A Pathogenic ★ same condition
DYNC2LI1 p.Arg207Ter Pathogenic ★ same condition
DYNC2LI1 p.Met1Thr Pathogenic ★ same condition
DYNC2LI1 p.Thr220Ile Pathogenic ★ ⚠ same condition
DYNC2LI1 c.127-8A>G 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/dync2li1-p-leu6phe (accessed [today's date]).

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