# NM_000325.6(PITX2):c.264del (p.Lys89fs)

https://sugi.bio/variant/pitx2-p-lys89fs

## Summary

**PITX2 p.Lys89fs (c.264del)** is classified **Pathogenic** in PITX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-29). No gnomAD frequency available for this variant; Associated with anterior segment dysgenesis 4.

**At a glance:** Pathogenic · review: Single submitter · rsID rs1729007624 · 1 submitter · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the PITX2 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to anterior segment dysgenesis 4.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0003026/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PITX2](https://sugi.bio/atlas/gene/PITX2/) |
| Protein change (HGVS p.) | p.Lys89fs |
| Coding change (HGVS c.) | c.264del |
| MANE Select transcript | [NM_000325](https://www.ncbi.nlm.nih.gov/nuccore/NM_000325) |
| dbSNP | [rs1729007624](https://www.ncbi.nlm.nih.gov/snp/rs1729007624/) |
| Variant type | Deletion |
| Location | chr4:110621311-110621311 (GRCh38) |
| ClinVar | [VCV837823](https://www.ncbi.nlm.nih.gov/clinvar/variation/837823/) |

**All HGVS expressions:** `NC_000004.11:g.111542467del`, `NC_000004.12:g.110621311del`, `NG_007120.1:g.21042del`, `NM_000325.6:c.264del`, `NM_001204397.2:c.243del`, `NM_001204398.1:c.243del`, `NM_001204399.1:c.105del`, `NM_153426.3:c.243del`, `NM_153427.3:c.105del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 7.821, GERP 2.65, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.41, pLI 0.99745), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 3**, so the transcript is predicted to undergo NMD.
- 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: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**PITX2** population constraint: LOEUF 0.41, pLI 0.99745, missense-Z 2.2361; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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):

- **anterior segment dysgenesis 4** — Definitive (AD)

## Protein context {#protein}

Residue **89** lies in a DNA-binding region; the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 62.59, 19% of residues very-high.

**3 experimental structure(s)** (PDB): [2L7F](https://www.rcsb.org/structure/2L7F), [2L7M](https://www.rcsb.org/structure/2L7M), [2LKX](https://www.rcsb.org/structure/2LKX) — incl. mutant structure 2L7M.

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

*Describes the biological roles of PITX2 (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:** PITX2's established molecular role includes transcription cis-regulatory region binding. p.Lys89fs falls in a DNA-binding region.


### Pathways affected {#pathways}

PITX2 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [TFAP2 (AP-2) family regulates transcription of other transcription factors](https://reactome.org/content/detail/R-HSA-8866906) | other |

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

**Molecular function:** transcription cis-regulatory region binding, DNA-binding transcription factor activity, RNA polymerase II-specific, DNA-binding transcription repressor activity, RNA polymerase II-specific, DNA-binding transcription factor activity, identical protein binding, protein homodimerization activity.

**Biological process:** negative regulation of transcription by RNA polymerase II, regulation of DNA-templated transcription, regulation of transcription by RNA polymerase II, deltoid tuberosity development, odontogenesis, camera-type eye development.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-07-29.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-07-29 |

## Associated conditions {#conditions}

[anterior segment dysgenesis 4](https://sugi.bio/atlas/disease/anterior-segment-dysgenesis-4/), [Axenfeld-Rieger syndrome type 1](https://sugi.bio/atlas/disease/axenfeld-rieger-syndrome-type-1/).

**Reported phenotype names (ClinVar):** Anterior segment dysgenesis 4, Axenfeld-Rieger syndrome type 1, IRIDOGONIODYSGENESIS SYNDROME, Rieger syndrome type 1.

## Similar variants {#similar}

Related PITX2 variant pages (same residue, condition, or type): [PITX2 p.Gln172fs](/variant/pitx2-p-gln172fs), [PITX2 p.Tyr280fs](/variant/pitx2-p-tyr280fs), [PITX2 p.Asn168fs](/variant/pitx2-p-asn168fs), [PITX2 p.Asn222fs](/variant/pitx2-p-asn222fs), [PITX2 p.Asp175fs](/variant/pitx2-p-asp175fs), [PITX2 p.Ile125fs](/variant/pitx2-p-ile125fs), [PITX2 p.Ser101fs](/variant/pitx2-p-ser101fs), [PITX2 p.Ser290fs](/variant/pitx2-p-ser290fs).

### 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 837823). 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.*