# NM_005918.4(MDH2):c.442A>T (p.Ile148Phe)

https://sugi.bio/variant/mdh2-p-ile148phe

## Summary

**MDH2 p.Ile148Phe (c.442A>T)** is classified **Uncertain significance** in MDH2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-18). AlphaMissense: likely pathogenic (0.8726); Ultra-rare (popmax 0.0307%, afr); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs375411208 · 3 submitters · 1 linked condition · AlphaMissense likely pathogenic · ultra-rare (popmax 0.0307%, afr)

## For patients & families {#patients}

This is a change in the MDH2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 submitters, and is linked to Inborn genetic diseases.

*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 | [MDH2](https://sugi.bio/atlas/gene/MDH2/) |
| Protein change (HGVS p.) | p.Ile148Phe |
| Coding change (HGVS c.) | c.442A>T |
| MANE Select transcript | [NM_005918](https://www.ncbi.nlm.nih.gov/nuccore/NM_005918) |
| dbSNP | [rs375411208](https://www.ncbi.nlm.nih.gov/snp/rs375411208/) |
| Variant type | single nucleotide variant |
| Location | chr7:76060385-76060385 (GRCh38) |
| ClinVar | [VCV1379043](https://www.ncbi.nlm.nih.gov/clinvar/variation/1379043/) |

**All HGVS expressions:** `NC_000007.13:g.75689703A>T`, `NC_000007.14:g.76060385A>T`, `NG_052976.1:g.17367A>T`, `NM_001282403.2:c.429+2307A>T`, `NM_001282404.2:c.121A>T`, `NM_005918.4:c.442A>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.8726)
- REVEL 0.399 (indeterminate)
- SaProt LLR -9.217 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate
- SpliceAI predicts **acceptor loss** (Δ 0.28) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 8.055, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 25.6**. 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 0.97** across the covering region of the MANE Select transcript (76,048,161–76,066,407), spanning 18,246 bp. Chi-square p 0.54. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.28**, donor loss **0.00**, acceptor gain **0.16**, donor gain **0.00**. Largest is acceptor loss, 12 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.16**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.41** (loss), gain 0.38 / loss 0.41. 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 **0.0307%** (afr) · FAF95 0.021% · FAF99 0.0178% · 23/74,918 in the highest group · 26/1,614,014 alleles overall — ultra-rare (popmax 0.0307%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0307% | 3,257 |
| Admixed American | 0.00167% | 60,004 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,474 |
| South Asian | 0.0011% | 91,090 |

*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}

**MDH2** population constraint: LOEUF 0.984, pLI 1.1219e-06, missense-Z 0.34026. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **148** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 93.49, 87% of residues very-high.

**7 experimental structure(s)** (PDB): [2DFD](https://www.rcsb.org/structure/2DFD), [4WLE](https://www.rcsb.org/structure/4WLE), [4WLF](https://www.rcsb.org/structure/4WLF), [4WLN](https://www.rcsb.org/structure/4WLN), [4WLO](https://www.rcsb.org/structure/4WLO), [4WLU](https://www.rcsb.org/structure/4WLU).

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

*Describes the biological roles of MDH2 (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:** MDH2's established molecular role includes RNA binding.


### Pathways affected {#pathways}

MDH2 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Citric acid cycle (TCA cycle)](https://reactome.org/content/detail/R-HSA-71403) | curated |
| [Malate-aspartate shuttle](https://reactome.org/content/detail/R-HSA-9856872) | curated |
| [Mitochondrial protein degradation](https://reactome.org/content/detail/R-HSA-9837999) | curated |

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

**Molecular function:** RNA binding, L-malate dehydrogenase (NAD+) activity.

**Biological process:** tricarboxylic acid cycle, malate metabolic process, aerobic respiration, malate-aspartate shuttle.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-03-18.

**Submitter consensus:** unanimous (3/3 Uncertain significance).

**Submission history:** 3 submissions (2022–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-07-21 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-10-15 |
| Dasa | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-03-18 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

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

## Similar variants {#similar}

Related MDH2 variant pages (same residue, condition, or type): [MDH2 p.Ile148Met](/variant/mdh2-p-ile148met), [MDH2 p.Ala135Gly](/variant/mdh2-p-ala135gly), [MDH2 p.Ala141Thr](/variant/mdh2-p-ala141thr), [MDH2 p.Ala177Thr](/variant/mdh2-p-ala177thr), [MDH2 p.Ala21Val](/variant/mdh2-p-ala21val), [MDH2 p.Ala242Val](/variant/mdh2-p-ala242val), [MDH2 p.Ala256Thr](/variant/mdh2-p-ala256thr), [MDH2 p.Ala325Val](/variant/mdh2-p-ala325val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 2026-10-14); 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 1379043). 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.*