# NM_003620.4(PPM1D):c.1806_1809del (p.Cys603fs)

https://sugi.bio/variant/ppm1d-p-cys603fs

## Summary

**PPM1D p.Cys603fs (c.1806_1809del)** is classified **Uncertain significance** in PPM1D (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-01). Very rare (popmax 0.00439%, sas).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs745470366 · 1 submitter · very rare (popmax 0.00439%, sas)

## For patients & families {#patients}

This is a change in the PPM1D gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [PPM1D](https://sugi.bio/atlas/gene/PPM1D/) |
| Protein change (HGVS p.) | p.Cys603fs |
| Coding change (HGVS c.) | c.1806_1809del |
| MANE Select transcript | [NM_003620](https://www.ncbi.nlm.nih.gov/nuccore/NM_003620) |
| dbSNP | [rs745470366](https://www.ncbi.nlm.nih.gov/snp/rs745470366/) |
| Variant type | Deletion |
| Location | chr17:60663537-60663540 (GRCh38) |
| ClinVar | [VCV2647994](https://www.ncbi.nlm.nih.gov/clinvar/variation/2647994/) |

**All HGVS expressions:** `LRG_770:g.68348_68351del`, `LRG_770t1:c.1806_1809del`, `NC_000017.10:g.58740901_58740904del`, `NC_000017.11:g.60663540_60663543del`, `NG_023265.1:g.68348_68351del`, `NM_003620.4:c.1806_1809del`

## 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 7.607, GERP 2.26, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.183, pLI 3.7145e-17. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in the last exon (6 of 6)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- CADD: **PHRED 34.0**. 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: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00439%** (sas) · FAF95 0.00143% · FAF99 0.000891% · 4/91,060 in the highest group · 9/1,607,778 alleles overall — very rare (popmax 0.00439%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00439% | 22,765 |
| Admixed American | 0.00167% | 59,950 |
| European (non-Finnish) | 0.000339% | 294,734 |

*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}

**PPM1D** population constraint: LOEUF 1.183, pLI 3.7145e-17, missense-Z 2.7759; ClinGen dosage — haploinsufficiency 0, triplosensitivity 0 (0–3 scale). *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):

- **syndromic intellectual disability** — Definitive (AD)

## Protein context {#protein}

Residue **603** lies in a UniProt-annotated variant site (in jdvs); a UniProt-annotated variant site (in oc; may be associated with disease susceptibility); a UniProt-annotated variant site (in bc; may be associated with disease susceptibility; gain-of-function mutation that results in increased negative regulation of p53 expression in response to ionizing radiation exposure); a UniProt-annotated variant site (in bc; may be associated with disease susceptibility).

AlphaFold model confidence (whole protein): pLDDT 68.15, 43% of residues very-high.

**1 experimental structure(s)** (PDB): [8T2J](https://www.rcsb.org/structure/8T2J).

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

*Describes the biological roles of PPM1D (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:** PPM1D's established molecular role includes protein serine/threonine phosphatase activity.


### Pathways affected {#pathways}

PPM1D participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Transcriptional regulation by RUNX2](https://reactome.org/content/detail/R-HSA-8878166) | curated |

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

**Molecular function:** protein serine/threonine phosphatase activity, mitogen-activated protein kinase binding.

**Biological process:** peptidyl-threonine dephosphorylation, negative regulation of gene expression, epigenetic.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-05-01.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| CeGaT Center for Human Genetics Tuebingen | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-05-01 |

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

## Similar variants {#similar}

Related PPM1D variant pages (same residue, condition, or type): [PPM1D p.Cys603Tyr](/variant/ppm1d-p-cys603tyr), [PPM1D p.Arg536fs](/variant/ppm1d-p-arg536fs), [PPM1D p.Pro413fs](/variant/ppm1d-p-pro413fs), [PPM1D p.Tyr401fs](/variant/ppm1d-p-tyr401fs), [PPM1D p.Arg429_Val430insTer](/variant/ppm1d-p-arg429-val430inster), [PPM1D p.Asn431_Ser432insTer](/variant/ppm1d-p-asn431-ser432inster), [PPM1D p.Cys407fs](/variant/ppm1d-p-cys407fs), [PPM1D p.Cys478fs](/variant/ppm1d-p-cys478fs).

### 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 2647994). 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.*