# NM_033428.3(DMAC1):c.254C>T (p.Thr85Met)

https://sugi.bio/variant/dmac1-p-thr85met

## Summary

**DMAC1 p.Thr85Met (c.254C>T)** is classified **Uncertain significance** in DMAC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-14). Very rare (popmax 0.00167%, amr).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs766111760 · 1 submitter · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the DMAC1 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 | [DMAC1](https://sugi.bio/atlas/gene/DMAC1/) |
| Protein change (HGVS p.) | p.Thr85Met |
| Coding change (HGVS c.) | c.254C>T |
| MANE Select transcript | [NM_033428](https://www.ncbi.nlm.nih.gov/nuccore/NM_033428) |
| dbSNP | [rs766111760](https://www.ncbi.nlm.nih.gov/snp/rs766111760/) |
| Variant type | single nucleotide variant |
| Location | chr9:7799481-7799481 (GRCh38) |
| ClinVar | [VCV3082974](https://www.ncbi.nlm.nih.gov/clinvar/variation/3082974/) |

**All HGVS expressions:** `NC_000009.11:g.7799481G>A`, `NC_000009.12:g.7799481G>A`, `NG_115918.1:g.40G>A`, `NM_001318058.2:c.254C>T`, `NM_001318059.2:c.188+66C>T`, `NM_033428.3:c.254C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 0.613, GERP -2.01 — weakly conserved position
- CADD: **PHRED 9.869**. 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 1.38** across the covering region of the MANE Select transcript (7,798,576–7,799,734), spanning 1,158 bp. Chi-square p 1.7e-06. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.20 donor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00167%** (amr) · FAF95 0.0005% · FAF99 0.000366% · 1/59,986 in the highest group · 14/1,612,748 alleles overall — very rare (popmax 0.00167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00321% | 31,184 |
| Admixed American (grpmax) | 0.00167% | 59,986 |
| European (non-Finnish) | 0.000932% | 107,272 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**DMAC1** population constraint: LOEUF 1.842, pLI 1.237e-05, missense-Z -1.6454. *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 60.00, 0% of residues very-high.

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

*Describes the biological roles of DMAC1 (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}

DMAC1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Complex I biogenesis](https://reactome.org/content/detail/R-HSA-6799198) | curated |

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

**Biological process:** mitochondrial respiratory chain complex I assembly.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-10-14.

**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 | 2021-10-14 |

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

## Similar variants {#similar}

Related DMAC1 variant pages (same residue, condition, or type): [DMAC1 p.Ala21Gly](/variant/dmac1-p-ala21gly), [DMAC1 p.Ala24Gly](/variant/dmac1-p-ala24gly), [DMAC1 p.Ala30Ser](/variant/dmac1-p-ala30ser), [DMAC1 p.Ala39Gly](/variant/dmac1-p-ala39gly), [DMAC1 p.Arg110Cys](/variant/dmac1-p-arg110cys), [DMAC1 p.Arg110His](/variant/dmac1-p-arg110his), [DMAC1 p.Arg42His](/variant/dmac1-p-arg42his), [DMAC1 p.Gln86Arg](/variant/dmac1-p-gln86arg).

### 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 3082974). 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.*