# NM_024101.7(MLPH):c.591C>T (p.Phe197=)

https://sugi.bio/variant/mlph-p-phe197

## Summary

**MLPH p.Phe197= (c.591C>T)** is classified **Likely benign** in MLPH (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-04). Very rare (popmax 0.00446%, eas).

**At a glance:** Likely benign · review: Single submitter · rsID rs766524828 · 1 submitter · very rare (popmax 0.00446%, eas)

## For patients & families {#patients}

This is a change in the MLPH gene that is classified as likely benign — not considered disease-causing, 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 | [MLPH](https://sugi.bio/atlas/gene/MLPH/) |
| Protein change (HGVS p.) | p.Phe197= |
| Coding change (HGVS c.) | c.591C>T |
| MANE Select transcript | [NM_024101](https://www.ncbi.nlm.nih.gov/nuccore/NM_024101) |
| dbSNP | [rs766524828](https://www.ncbi.nlm.nih.gov/snp/rs766524828/) |
| Variant type | single nucleotide variant |
| Location | chr2:237519945-237519945 (GRCh38) |
| ClinVar | [VCV1924709](https://www.ncbi.nlm.nih.gov/clinvar/variation/1924709/) |

**All HGVS expressions:** `LRG_83:g.37659C>T`, `LRG_83t1:c.591C>T`, `NC_000002.11:g.238428588C>T`, `NC_000002.12:g.237519945C>T`, `NG_007286.1:g.37659C>T`, `NG_098107.1:g.664C>T`, `NM_001042467.3:c.591C>T`, `NM_001281473.2:c.555+1297C>T`, `NM_001281474.2:c.591C>T`, `NM_024101.7:c.591C>T`, `NR_104019.2:n.802C>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 -4.192, GERP -2.31 — fast-evolving / accelerated position
- CADD: **PHRED 1.062**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.21 acceptor 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 **0.00446%** (eas) · FAF95 0.000739% · FAF99 0.000276% · 2/44,876 in the highest group · 10/1,614,024 alleles overall — very rare (popmax 0.00446%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00446% | 22,438 |
| South Asian | 0.0022% | 45,541 |
| European (non-Finnish) | 0.000508% | 196,668 |

*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 **197** 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.Phe197= 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-08-04.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-08-04 |

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

## Similar variants {#similar}

Related MLPH variant pages (same residue, condition, or type): [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), [MLPH p.Asp194Asn](/variant/mlph-p-asp194asn).

### 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 1924709). 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.*