# NM_024101.7(MLPH):c.1539G>T (p.Pro513=)

https://sugi.bio/variant/mlph-p-pro513

## Summary

**MLPH p.Pro513= (c.1539G>T)** is classified **Conflicting classifications of pathogenicity** in MLPH (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-04-22). Very rare (popmax 0.000346%, nfe).

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs151070956 · 2 submitters · very rare (popmax 0.000346%, nfe)

## For patients & families {#patients}

This is a change in the MLPH gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters.

*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 | [MLPH](https://sugi.bio/atlas/gene/MLPH/) |
| Protein change (HGVS p.) | p.Pro513= |
| Coding change (HGVS c.) | c.1539G>T |
| MANE Select transcript | [NM_024101](https://www.ncbi.nlm.nih.gov/nuccore/NM_024101) |
| dbSNP | [rs151070956](https://www.ncbi.nlm.nih.gov/snp/rs151070956/) |
| Variant type | single nucleotide variant |
| Location | chr2:237542659-237542659 (GRCh38) |
| ClinVar | [VCV1336244](https://www.ncbi.nlm.nih.gov/clinvar/variation/1336244/) |

**All HGVS expressions:** `LRG_83:g.60373G>T`, `NC_000002.11:g.238451302G>T`, `NC_000002.12:g.237542659G>T`, `NG_007286.1:g.60373G>T`, `NM_001042467.3:c.1455G>T`, `NM_001281473.2:c.1179G>T`, `NM_001281474.2:c.1110G>T`, `NM_024101.7:c.1539G>T`, `NR_104019.2:n.1750G>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.48) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -0.074, GERP -3.59, phastCons 0.235 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 19.47**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.05**, acceptor gain **0.00**, donor gain **0.48**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.05**, acceptor gain **0.00**, donor gain **0.48**.
- Pangolin: Δ**0.33** (gain), gain 0.33 / loss 0.11. 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 **0.000346%** (nfe) · FAF95 8.1e-05% · FAF99 5.5e-05% · 4/1,156,540 in the highest group · 4/1,567,524 alleles overall — very rare (popmax 0.000346%, 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}

**MLPH** population constraint: LOEUF 0.856, pLI 1.1798e-11, missense-Z 0.59986; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *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 **513** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 61.58, 25% of residues very-high.

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

*Describes the biological roles of MLPH (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:** MLPH's established molecular role includes myosin binding. p.Pro513= falls in the disordered region.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Regulation of MITF-M-dependent genes involved in pigmentation](https://reactome.org/content/detail/R-HSA-9824585) | curated |

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

**Molecular function:** myosin binding, protein-macromolecule adaptor activity, small GTPase binding.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2022-04-22.

**Submitter consensus:** conflicting (1 Likely benign, 1 Uncertain significance).

**Submission history:** 2 submissions (2017–2022); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genetic Services Laboratory, University of Chicago | Likely benign | criteria provided, single submitter | clinical testing | 2017-09-13 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-04-22 |

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

## Similar variants {#similar}

Related MLPH variant pages (same residue, condition, or type): [MLPH p.Pro513Leu](/variant/mlph-p-pro513leu), [MLPH p.Arg35Gln](/variant/mlph-p-arg35gln), [MLPH p.Arg35Trp](/variant/mlph-p-arg35trp), [MLPH p.Ala236Thr](/variant/mlph-p-ala236thr), [MLPH p.Ala520Ser](/variant/mlph-p-ala520ser), [MLPH p.Arg375Cys](/variant/mlph-p-arg375cys), [MLPH p.Arg507Trp](/variant/mlph-p-arg507trp), [MLPH p.Arg518Gly](/variant/mlph-p-arg518gly).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 1336244). 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.*