# NM_014889.4(PITRM1):c.223A>C (p.Arg75=)

https://sugi.bio/variant/pitrm1-p-arg75

## Summary

**PITRM1 p.Arg75= (c.223A>C)** is classified **Conflicting classifications of pathogenicity** in PITRM1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-10-01). Rare (popmax 0.115%, mid).

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs767590298 · 2 submitters · rare (popmax 0.115%, mid)

## For patients & families {#patients}

This is a change in the PITRM1 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 | [PITRM1](https://sugi.bio/atlas/gene/PITRM1/) |
| Protein change (HGVS p.) | p.Arg75= |
| Coding change (HGVS c.) | c.223A>C |
| MANE Select transcript | [NM_014889](https://www.ncbi.nlm.nih.gov/nuccore/NM_014889) |
| dbSNP | [rs767590298](https://www.ncbi.nlm.nih.gov/snp/rs767590298/) |
| Variant type | single nucleotide variant |
| Location | chr10:3166979-3166979 (GRCh38) |
| ClinVar | [VCV2044687](https://www.ncbi.nlm.nih.gov/clinvar/variation/2044687/) |

**All HGVS expressions:** `NC_000010.10:g.3209171T>G`, `NC_000010.11:g.3166979T>G`, `NG_052908.1:g.10863A>C`, `NM_001242307.2:c.223A>C`, `NM_001242309.1:c.127A>C`, `NM_001347725.2:c.223A>C`, `NM_001347726.2:c.-349A>C`, `NM_001347727.2:c.-349A>C`, `NM_001347728.2:c.-1078A>C`, `NM_001347729.1:c.199A>C`, `NM_001347730.1:c.199A>C`, `NM_014889.4:c.223A>C`, `NR_144638.2:n.233A>C`, `NR_144639.2:n.233A>C`, `NR_144640.2:n.233A>C`, `NR_144641.2:n.233A>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.80) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.246, GERP 0.396 — weakly conserved position
- CADD: **PHRED 3.888**. 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 **0.80**, acceptor gain **0.00**, donor gain **0.02**. Largest is donor loss, 1 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.02**.
  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.*
- Population frequency (gnomAD v4.1): grpmax **0.115%** (mid) · FAF95 0.054% · FAF99 0.0383% · 7/6,080 in the highest group · 77/1,611,472 alleles overall — rare (popmax 0.115%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.115% | 869 |
| Remaining individuals (not grpmax-eligible) | 0.00641% | 15,599 |
| European (non-Finnish) | 0.00534% | 18,710 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00339% | 29,514 |
| South Asian | 0.00221% | 45,191 |

*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 **75** lies in a β-strand.

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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-10-01.

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

**Submission history:** 2 submissions (2022–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-09-15 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-01 |

**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 2044687). 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.*