# NM_014672.4(PRORP):c.426T>G (p.Ser142Arg)

https://sugi.bio/variant/prorp-p-ser142arg

## Summary

**PRORP p.Ser142Arg (c.426T>G)** is classified **Likely benign** in PRORP (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-12). AlphaMissense: likely benign (0.236); Very rare (popmax 0.00381%, nfe).

**At a glance:** Likely benign · review: Single submitter · rsID rs750804324 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00381%, nfe)

## For patients & families {#patients}

This is a change in the PRORP 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 | [PRORP](https://sugi.bio/atlas/gene/PRORP/) |
| Protein change (HGVS p.) | p.Ser142Arg |
| Coding change (HGVS c.) | c.426T>G |
| MANE Select transcript | [NM_014672](https://www.ncbi.nlm.nih.gov/nuccore/NM_014672) |
| dbSNP | [rs750804324](https://www.ncbi.nlm.nih.gov/snp/rs750804324/) |
| Variant type | single nucleotide variant |
| Location | chr14:35123671-35123671 (GRCh38) |
| ClinVar | [VCV2561330](https://www.ncbi.nlm.nih.gov/clinvar/variation/2561330/) |

**All HGVS expressions:** `NC_000014.8:g.35592877T>G`, `NC_000014.9:g.35123671T>G`, `NM_001256678.2:c.426T>G`, `NM_001256679.2:c.141T>G`, `NM_001256680.2:c.-131+761T>G`, `NM_001256681.2:c.-83+761T>G`, `NM_001414503.1:c.426T>G`, `NM_014672.4:c.426T>G`, `NR_182666.1:n.934T>G`, `NR_182667.1:n.804T>G`, `NR_182668.1:n.804T>G`, `NR_182669.1:n.936T>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.236)
- REVEL 0.062 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.924 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor gain** (Δ 0.35) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -0.698, GERP -3.5, phastCons 0.005 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 2.276**. 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 0.94** across the covering region of the MANE Select transcript (35,123,246–35,273,563), spanning 150,317 bp. Chi-square p 0.092. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.35**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.35**.
- Pangolin: Δ**0.42** (gain), gain 0.42 / loss 0.00. 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 **0.00381%** (nfe) · FAF95 0.00291% · FAF99 0.0026% · 45/1,180,046 in the highest group · 46/1,614,078 alleles overall — very rare (popmax 0.00381%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00381% | 26,223 |
| African / African-American | 0.00133% | 74,944 |

*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}

**PRORP** population constraint: LOEUF 0.999, pLI 1.7105e-10, missense-Z 1.1135. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **mitochondrial disease** — Definitive (AR)

## Protein context {#protein}

Residue **142** lies in a turn.

AlphaFold model confidence (whole protein): pLDDT 79.19, 60% of residues very-high.

**5 experimental structure(s)** (PDB): [4ROU](https://www.rcsb.org/structure/4ROU), [4XGL](https://www.rcsb.org/structure/4XGL), [4XGM](https://www.rcsb.org/structure/4XGM), [7ONU](https://www.rcsb.org/structure/7ONU), [8CBK](https://www.rcsb.org/structure/8CBK).

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

*Describes the biological roles of PRORP (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:** PRORP's established molecular role includes ribonuclease P activity.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [rRNA processing in the mitochondrion](https://reactome.org/content/detail/R-HSA-8868766) | curated |
| [tRNA modification in the mitochondrion](https://reactome.org/content/detail/R-HSA-6787450) | curated |
| [tRNA processing in the mitochondrion](https://reactome.org/content/detail/R-HSA-6785470) | curated |

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

**Molecular function:** ribonuclease P activity.

**Biological process:** mitochondrial tRNA 5'-end processing.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-06-12.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-06-12 |

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

## Similar variants {#similar}

Related PRORP variant pages (same residue, condition, or type): [PRORP p.Arg421Cys](/variant/prorp-p-arg421cys), [PRORP p.Arg502Gln](/variant/prorp-p-arg502gln), [PRORP p.Asn412Ser](/variant/prorp-p-asn412ser), [PRORP p.Lys76=](/variant/prorp-p-lys76), [PRORP p.Ala434Asp](/variant/prorp-p-ala434asp), [PRORP c.-1A>G](/variant/prorp-c-minus-1a-g), [PRORP p.Ala104Val](/variant/prorp-p-ala104val), [PRORP p.Ala158Thr](/variant/prorp-p-ala158thr).

### 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 2561330). 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.*