# NM_174910.3(DYNLT2):c.340G>C (p.Asp114His)

https://sugi.bio/variant/dynlt2-p-asp114his

## Summary

**DYNLT2 p.Asp114His (c.340G>C)** is classified **Uncertain significance** in DYNLT2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-30). AlphaMissense: likely benign (0.1885); Ultra-rare (popmax 0.0655%, amr).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0655%, amr)

## For patients & families {#patients}

This is a change in the DYNLT2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [DYNLT2](https://sugi.bio/atlas/gene/DYNLT2/) |
| Protein change (HGVS p.) | p.Asp114His |
| Coding change (HGVS c.) | c.340G>C |
| MANE Select transcript | [NM_174910](https://www.ncbi.nlm.nih.gov/nuccore/NM_174910) |
| Variant type | single nucleotide variant |
| Location | chr6:169743226-169743226 (GRCh38) |
| ClinVar | [VCV4245892](https://www.ncbi.nlm.nih.gov/clinvar/variation/4245892/) |

**All HGVS expressions:** `NC_000006.11:g.170143322C>G`, `NC_000006.12:g.169743226C>G`, `NM_174910.3:c.340G>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1885)
- REVEL 0.115 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -9.693 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor loss** (Δ 0.47) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 4.677, GERP 4.84, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 25.5**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 1.05** across the covering region of the MANE Select transcript (169,740,188–169,751,458), spanning 11,270 bp. Chi-square p 0.45. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.47**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.47**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.40** (loss), gain 0.00 / loss 0.40. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0655%** (amr) · FAF95 0.0473% · FAF99 0.0412% · 31/47,362 in the highest group · 31/1,475,608 alleles overall — ultra-rare (popmax 0.0655%, amr).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**DYNLT2** population constraint: LOEUF 1.376, pLI 2.6813e-07, missense-Z -0.3758. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 77.20, 45% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of DYNLT2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*


### Pathways affected {#pathways}

DYNLT2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Intraflagellar transport](https://reactome.org/content/detail/R-HSA-5620924) | curated |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-06-30.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-06-30 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related DYNLT2 variant pages (same residue, condition, or type): [DYNLT2 p.Asp114Gly](/variant/dynlt2-p-asp114gly), [DYNLT2 p.Ala130Val](/variant/dynlt2-p-ala130val), [DYNLT2 p.Ala164Val](/variant/dynlt2-p-ala164val), [DYNLT2 p.Ala178Thr](/variant/dynlt2-p-ala178thr), [DYNLT2 p.Ala68Thr](/variant/dynlt2-p-ala68thr), [DYNLT2 p.Ala84Ser](/variant/dynlt2-p-ala84ser), [DYNLT2 p.Arg132Cys](/variant/dynlt2-p-arg132cys), [DYNLT2 p.Arg144Cys](/variant/dynlt2-p-arg144cys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 4245892). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*