Is DYNC2LI1 p.Phe33Ser (c.98T>C) pathogenic?

DYNC2LI1 p.Phe33Ser (c.98T>C) is classified Benign in DYNC2LI1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.0476); Common (popmax 83.4%, afr) — too common for a highly-penetrant pathogenic allele; Associated with short-rib thoracic dysplasia 15 with polydactyly.

What condition is associated with DYNC2LI1 p.Phe33Ser (c.98T>C)?

DYNC2LI1 p.Phe33Ser (c.98T>C) is associated with short-rib thoracic dysplasia 15 with polydactyly (ClinVar).

What do computational predictors say about DYNC2LI1 p.Phe33Ser (c.98T>C)?

AlphaMissense predicts likely benign (score 0.0476) — an in-silico prediction, not a clinical call.

DYNC2LI1 p.Phe33Ser

Q: How common is DYNC2LI1 p.Phe33Ser (c.98T>C) in the general population?

DYNC2LI1 p.Phe33Ser (c.98T>C) is common (popmax 83.4%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.98T>C · rs2288709 · VCV1255528

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0476 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 83.4%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

short-rib thoracic dysplasia 15 with polydactyly

Computational evidence

Protein change
AlphaMissense	0.0476	likely benign
REVEL	0.273	benign-leaning
SaProt	LLR -5.85	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.8	GERP 1.1, phastCons 1
Regional constraint	o/e 1.17	unconstrained · MANE · 36 kb · p 0.00038 · regional, not allelic
Overall
CADD	18.29	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 83.4% African / African-American · 61,871/74,228 alleles

Filtering AF 82.8% ClinGen BA1/BS1 input FAF95, joint · FAF99 82.6%

Overall 39.6% 631,938/1,594,682 alleles · common exomes 555,749/1,442,614 · genomes 76,189/152,068 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	83.4%	1
South Asian	52.5%	2
Admixed American	50.5%	2
Middle Eastern	48.9%	2
Ashkenazi Jewishnot grpmax-eligible	41.5%	2
Remaining individualsnot grpmax-eligible	40.3%	2
European (non-Finnish)	36.4%	3
Finnishnot grpmax-eligible	34.5%	3
Amishnot grpmax-eligible	23.1%	4
East Asian	16.9%	6

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.Phe33Ser
Coding: c.98T>C
MANE Select: NM_016008
dbSNP: rs2288709
Type: single nucleotide variant
Location: chr2:43776871 (GRCh38)
Gene constraint: LOEUF 1.028 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.49 · 3 PDB
Residue 33: a UniProt-annotated variant site (in)

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.Leu6Phe Likely 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-phe33ser (accessed [today's date]).

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