# NM_005996.4(TBX3):c.959C>T (p.Ser320Phe)

https://sugi.bio/variant/tbx3-p-ser320phe

## Summary

**TBX3 p.Ser320Phe (c.959C>T)** is classified **Uncertain significance** in TBX3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-20). AlphaMissense: ambiguous (0.5207); Very rare (popmax 0.00133%, afr); Associated with ulnar-mammary syndrome.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1396893876 · 1 submitter · 1 linked condition · AlphaMissense ambiguous · very rare (popmax 0.00133%, afr)

## For patients & families {#patients}

This is a change in the TBX3 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to ulnar-mammary syndrome.

*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/0000118/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [TBX3](https://sugi.bio/atlas/gene/TBX3/) |
| Protein change (HGVS p.) | p.Ser320Phe |
| Coding change (HGVS c.) | c.959C>T |
| MANE Select transcript | [NM_005996](https://www.ncbi.nlm.nih.gov/nuccore/NM_005996) |
| dbSNP | [rs1396893876](https://www.ncbi.nlm.nih.gov/snp/rs1396893876/) |
| Variant type | single nucleotide variant |
| Location | chr12:114676393-114676393 (GRCh38) |
| ClinVar | [VCV1465536](https://www.ncbi.nlm.nih.gov/clinvar/variation/1465536/) |

**All HGVS expressions:** `NC_000012.11:g.115114198G>A`, `NC_000012.12:g.114676393G>A`, `NG_008315.1:g.12772C>T`, `NM_005996.4:c.959C>T`, `NM_016569.4:c.1019C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL are indeterminate here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.5207) — no call either way
- REVEL 0.562 (indeterminate)
- SaProt LLR -8.581 (tolerated)
- Conservation: phyloP 11.804, GERP 1.63, phastCons 1 — highly conserved
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **S340F** vs ClinVar **S320F**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 29.2**. 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 0.74** across the covering region of the MANE Select transcript (114,676,313–114,676,459), spanning 146 bp. Chi-square p 0.047. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00133%** (afr) · 1/74,932 in the highest group · 2/1,614,086 alleles overall — very rare (popmax 0.00133%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00133% | 74,932 |
| European (non-Finnish) | 8.47e-05% | 1,180,048 |

*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}

**TBX3** population constraint: LOEUF 0.468, pLI 0.99465, missense-Z 0.036562; 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):

- **ulnar-mammary syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **340** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 56.55, 23% of residues very-high.

**1 experimental structure(s)** (PDB): [1H6F](https://www.rcsb.org/structure/1H6F).

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

*Describes the biological roles of TBX3 (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:** TBX3's established molecular role includes RNA polymerase II cis-regulatory region sequence-specific DNA binding. p.Ser320Phe falls in the disordered region.


### Pathways affected {#pathways}

TBX3 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Transcriptional and post-translational regulation of MITF-M expression and activity](https://reactome.org/content/detail/R-HSA-9856649) | curated |

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

**Molecular function:** RNA polymerase II cis-regulatory region sequence-specific DNA binding, DNA-binding transcription repressor activity, RNA polymerase II-specific, DNA-binding transcription activator activity, RNA polymerase II-specific, sequence-specific DNA binding, sequence-specific double-stranded DNA binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, skeletal system development, endocardial cushion formation, positive regulation of cell population proliferation, anterior/posterior axis specification, embryo, animal organ morphogenesis.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-06-20.

**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 | 2022-06-20 |

## Associated conditions {#conditions}

[ulnar-mammary syndrome](https://sugi.bio/atlas/disease/ulnar-mammary-syndrome/).

**Reported phenotype names (ClinVar):** Ulnar-mammary syndrome, SCHINZEL SYNDROME, PALLISTER ULNAR-MAMMARY SYNDROME, Ulnar-mammary syndrome of Pallister.

## Similar variants {#similar}

Related TBX3 variant pages (same residue, condition, or type): [TBX3 p.Gln475Ter](/variant/tbx3-p-gln475ter), [TBX3 c.1710+3A>G](/variant/tbx3-c-1710-plus-3a-g), [TBX3 p.Ala158Thr](/variant/tbx3-p-ala158thr), [TBX3 p.Ala336Val](/variant/tbx3-p-ala336val), [TBX3 p.Ala357Pro](/variant/tbx3-p-ala357pro), [TBX3 p.Ala391Gly](/variant/tbx3-p-ala391gly), [TBX3 p.Ala470Thr](/variant/tbx3-p-ala470thr), [TBX3 p.Ala488Thr](/variant/tbx3-p-ala488thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 1465536). 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.*