# NM_000325.6(PITX2):c.517C>T (p.Pro173Ser)

https://sugi.bio/variant/pitx2-p-pro173ser

## Summary

**PITX2 p.Pro173Ser (c.517C>T)** is classified **Uncertain significance** in PITX2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-05). AlphaMissense: likely benign (0.3342); Absent from gnomAD v4.1; Associated with Axenfeld-Rieger syndrome type 1.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1728874429 · 1 submitter · 2 linked conditions · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the PITX2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Axenfeld-Rieger syndrome type 1.

*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/0010281/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.Pro173Ser |
| Coding change (HGVS c.) | c.517C>T |
| MANE Select transcript | [NM_000325](https://www.ncbi.nlm.nih.gov/nuccore/NM_000325) |
| dbSNP | [rs1728874429](https://www.ncbi.nlm.nih.gov/snp/rs1728874429/) |
| Variant type | single nucleotide variant |
| Location | chr4:110618583-110618583 (GRCh38) |
| ClinVar | [VCV2007681](https://www.ncbi.nlm.nih.gov/clinvar/variation/2007681/) |

**All HGVS expressions:** `NC_000004.11:g.111539739G>A`, `NC_000004.12:g.110618583G>A`, `NG_007120.1:g.23770C>T`, `NM_000325.6:c.517C>T`, `NM_001204397.2:c.496C>T`, `NM_001204398.1:c.496C>T`, `NM_001204399.1:c.358C>T`, `NM_153426.3:c.496C>T`, `NM_153427.3:c.358C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.3342)
- REVEL 0.843 (moderately pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -11.207 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** REVEL and SaProt call this damaging; AlphaMissense does not
- Conservation: phyloP 9.955, GERP 2.76, phastCons 1 — highly conserved (differs from AlphaMissense)
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **P166S** vs ClinVar **P173S**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- 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.*
- Regional missense constraint: **o/e 0.70** across the covering region of the MANE Select transcript (110,618,128–110,618,660), spanning 532 bp. Chi-square p 3.3e-06. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for PITX2 (187 scored positions, the nearest 13 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}


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.


### 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-04-05.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-04-05 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related PITX2 variant pages (same residue, condition, or type): [PITX2 c.411+1G>A](/variant/pitx2-c-411-plus-1g-a), [PITX2 c.412-11A>G](/variant/pitx2-c-412-minus-11a-g), [PITX2 c.412-2A>G](/variant/pitx2-c-412-minus-2a-g), [PITX2 p.Arg115His](/variant/pitx2-p-arg115his), [PITX2 p.Arg122His](/variant/pitx2-p-arg122his), [PITX2 p.Arg144Pro](/variant/pitx2-p-arg144pro), [PITX2 p.Arg144Trp](/variant/pitx2-p-arg144trp), [PITX2 p.Arg96Trp](/variant/pitx2-p-arg96trp).

### 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 2007681). 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.*