# NM_014889.4(PITRM1):c.1686T>C (p.Val562=)

https://sugi.bio/variant/pitrm1-p-val562

## Summary

**PITRM1 p.Val562= (c.1686T>C)** is classified **Likely benign** in PITRM1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-01). Ultra-rare (popmax 0.0318%, amr).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs777055355 · 2 submitters · ultra-rare (popmax 0.0318%, amr)

## For patients & families {#patients}

This is a change in the PITRM1 gene that is classified as likely benign — not considered disease-causing, 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 | [PITRM1](https://sugi.bio/atlas/gene/PITRM1/) |
| Protein change (HGVS p.) | p.Val562= |
| Coding change (HGVS c.) | c.1686T>C |
| MANE Select transcript | [NM_014889](https://www.ncbi.nlm.nih.gov/nuccore/NM_014889) |
| dbSNP | [rs777055355](https://www.ncbi.nlm.nih.gov/snp/rs777055355/) |
| Variant type | single nucleotide variant |
| Location | chr10:3151299-3151299 (GRCh38) |
| ClinVar | [VCV1554471](https://www.ncbi.nlm.nih.gov/clinvar/variation/1554471/) |

**All HGVS expressions:** `NC_000010.10:g.3193491A>G`, `NC_000010.11:g.3151299A>G`, `NG_052908.1:g.26543T>C`, `NM_001242307.2:c.1686T>C`, `NM_001242309.1:c.1590T>C`, `NM_001347725.2:c.1686T>C`, `NM_001347726.2:c.1071T>C`, `NM_001347727.2:c.1071T>C`, `NM_001347728.2:c.381T>C`, `NM_001347729.1:c.1662T>C`, `NM_001347730.1:c.1662T>C`, `NM_014889.4:c.1686T>C`, `NR_144638.2:n.1696T>C`, `NR_144639.2:n.1696T>C`, `NR_144640.2:n.1696T>C`, `NR_144641.2:n.1696T>C`

## 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 -1.323, GERP -3.27 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 0.394**. 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 (A>T, Δ0.23 donor gain), 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 **0.0318%** (amr) · FAF95 0.0208% · FAF99 0.0173% · 19/59,680 in the highest group · 19/1,611,168 alleles overall — ultra-rare (popmax 0.0318%, amr).

*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}

**PITRM1** population constraint: LOEUF 0.997, pLI 1.0799e-20, missense-Z -1.5936. *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 **562** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 94.44, 93% of residues very-high.

**8 experimental structure(s)** (PDB): [4L3T](https://www.rcsb.org/structure/4L3T), [4NGE](https://www.rcsb.org/structure/4NGE), [4RPU](https://www.rcsb.org/structure/4RPU), [6XOS](https://www.rcsb.org/structure/6XOS), [6XOT](https://www.rcsb.org/structure/6XOT), [6XOU](https://www.rcsb.org/structure/6XOU).

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

*Describes the biological roles of PITRM1 (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:** PITRM1's established molecular role includes metalloendopeptidase activity.


### Pathways affected {#pathways}

PITRM1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Mitochondrial protein import](https://reactome.org/content/detail/R-HSA-1268020) | curated |

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

**Molecular function:** metalloendopeptidase activity, metallopeptidase activity, zinc ion binding.

**Biological process:** proteolysis.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-01.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2021–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2021-12-21 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-01 |

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

## Similar variants {#similar}

Related PITRM1 variant pages (same residue, condition, or type): [PITRM1 p.Thr931Met](/variant/pitrm1-p-thr931met), [PITRM1 p.Ala1003Thr](/variant/pitrm1-p-ala1003thr), [PITRM1 p.Ala559Val](/variant/pitrm1-p-ala559val), [PITRM1 p.Ala887Val](/variant/pitrm1-p-ala887val), [PITRM1 p.Ala942Val](/variant/pitrm1-p-ala942val), [PITRM1 p.Ala965Thr](/variant/pitrm1-p-ala965thr), [PITRM1 p.Arg32Trp](/variant/pitrm1-p-arg32trp), [PITRM1 p.Arg545Gln](/variant/pitrm1-p-arg545gln).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 1554471). 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.*