# NM_001353214.3(DYM):c.233T>G (p.Ile78Ser)

https://sugi.bio/variant/dym-p-ile78ser

## Summary

**DYM p.Ile78Ser (c.233T>G)** is classified **Uncertain significance** in DYM (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-04). AlphaMissense: ambiguous (0.5471); Very rare (popmax 0.00212%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs770135743 · 1 submitter · AlphaMissense ambiguous · very rare (popmax 0.00212%, nfe)

## For patients & families {#patients}

This is a change in the DYM 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 | [DYM](https://sugi.bio/atlas/gene/DYM/) |
| Protein change (HGVS p.) | p.Ile78Ser |
| Coding change (HGVS c.) | c.233T>G |
| MANE Select transcript | [NM_001353214](https://www.ncbi.nlm.nih.gov/nuccore/NM_001353214) |
| dbSNP | [rs770135743](https://www.ncbi.nlm.nih.gov/snp/rs770135743/) |
| Variant type | single nucleotide variant |
| Location | chr18:49379719-49379719 (GRCh38) |
| ClinVar | [VCV1377059](https://www.ncbi.nlm.nih.gov/clinvar/variation/1377059/) |

**All HGVS expressions:** `NC_000018.10:g.49379719A>C`, `NC_000018.9:g.46906089A>C`, `NG_009239.2:g.86015T>G`, `NM_001353210.3:c.233T>G`, `NM_001353211.3:c.230T>G`, `NM_001353212.3:c.230T>G`, `NM_001353213.3:c.233T>G`, `NM_001353214.3:c.233T>G`, `NM_001353215.3:c.233T>G`, `NM_001353216.3:c.233T>G`, `NM_001374428.1:c.233T>G`, `NM_001374429.1:c.230T>G`, `NM_001374430.1:c.233T>G`, `NM_001374431.1:c.233T>G`, `NM_001374432.1:c.233T>G`, `NM_001374433.1:c.233T>G`, `NM_001374434.1:c.233T>G`, `NM_001374435.1:c.233T>G`, `NM_001374436.1:c.233T>G`, `NM_001374437.1:c.233T>G`, `NM_001374438.1:c.233T>G`, `NM_001374439.1:c.230T>G`, `NM_001374440.1:c.193+11874T>G`, `NM_001374441.1:c.193+11874T>G`, `NM_001374442.1:c.193+11874T>G`, `NM_001374443.1:c.193+11874T>G`, `NM_001374444.1:c.193+11874T>G`, `NM_017653.6:c.233T>G`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this damaging; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.5471) — no call either way
- REVEL 0.836 (moderately pathogenic-leaning)
- SaProt LLR -10.907 (damaging)
- → **In-silico consensus:** REVEL and SaProt both call this damaging; AlphaMissense makes no call
- SpliceAI predicts **donor gain** (Δ 0.56) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 9.329, GERP 2.06, phastCons 1 — highly conserved
- CADD: **PHRED 33.0**. 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 1.03** across the covering region of the MANE Select transcript (49,272,294–49,430,394), spanning 158,100 bp. Chi-square p 0.51. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.02**, donor loss **0.01**, acceptor gain **0.00**, donor gain **0.56**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.02**, donor loss **0.01**, acceptor gain **0.00**, donor gain **0.56**.
- Population frequency (gnomAD v4.1): grpmax **0.00212%** (nfe) · FAF95 0.00145% · FAF99 0.00123% · 25/1,179,550 in the highest group · 25/1,461,118 alleles overall — very rare (popmax 0.00212%, nfe).

*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}

**DYM** population constraint: LOEUF 1.081, pLI 7.9636e-21, missense-Z 0.92126; ClinGen dosage — haploinsufficiency 30, triplosensitivity 0 (0–3 scale). *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 87.91, 72% of residues very-high.

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

*Describes the biological roles of DYM (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.*

**How this variant is thought to act:** DYM's established molecular role includes enzyme binding.


### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** enzyme binding.

**Biological process:** Golgi organization, bone development.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-02-04.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-02-04 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related DYM variant pages (same residue, condition, or type): [DYM c.1728+2T>C](/variant/dym-c-1728-plus-2t-c), [DYM c.947-2A>G](/variant/dym-c-947-minus-2a-g), [DYM p.Arg204Ter](/variant/dym-p-arg204ter), [DYM p.Arg428Ter](/variant/dym-p-arg428ter), [DYM p.Arg588Ter](/variant/dym-p-arg588ter), [DYM p.Arg70Ter](/variant/dym-p-arg70ter), [DYM p.Gln306Ter](/variant/dym-p-gln306ter), [DYM p.Glu87Lys](/variant/dym-p-glu87lys).

### 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 1377059). 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.*