# NM_021973.3(HAND2):c.282del (p.Pro95fs)

https://sugi.bio/variant/hand2-p-pro95fs

## Summary

**HAND2 p.Pro95fs (c.282del)** is classified **Uncertain significance** in HAND2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-03-04). Very rare (popmax 0.00136%, afr); Associated with HAND2-related disorder.

**At a glance:** Uncertain significance · review: No assertion criteria · 1 submitter · 1 linked condition · very rare (popmax 0.00136%, afr)

## For patients & families {#patients}

This is a change in the HAND2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to HAND2-related disorder.

*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 | [HAND2](https://sugi.bio/atlas/gene/HAND2/) |
| Protein change (HGVS p.) | p.Pro95fs |
| Coding change (HGVS c.) | c.282del |
| MANE Select transcript | [NM_021973](https://www.ncbi.nlm.nih.gov/nuccore/NM_021973) |
| Variant type | Deletion |
| Location | chr4:173529008-173529008 (GRCh38) |
| ClinVar | [VCV3353539](https://www.ncbi.nlm.nih.gov/clinvar/variation/3353539/) |

**All HGVS expressions:** `NC_000004.11:g.174450165del`, `NC_000004.12:g.173529014del`, `NG_046954.1:g.6220del`, `NM_021973.3:c.282del`

## 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 11.646, GERP 1.74, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.601, pLI 0.88666. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 1 of 2**, 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.
- Repeat context: **simple_repeat** ((CCGGCGC)n). The alignment of this deletion is ambiguous inside a repeating unit, so the same change can be written several ways and a frequency lookup keyed on one representation can miss another. *A qualifier on how reliably this variant can be called and counted — not a pathogenicity signal.*
- Population frequency (gnomAD v4.1): grpmax **0.00136%** (afr) · 1/73,366 in the highest group · 2/1,591,320 alleles overall — very rare (popmax 0.00136%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00163% | 61,238 |
| African / African-American (grpmax) | 0.00136% | 73,366 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**HAND2** population constraint: LOEUF 0.601, pLI 0.88666, missense-Z -0.26935. *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):

- **HAND2 related congenital heart defect** — Moderate (AD)

## Protein context {#protein}

Residue **95** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 67.30, 22% of residues very-high.

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

*Describes the biological roles of HAND2 (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:** HAND2's established molecular role includes RNA polymerase II transcription regulatory region sequence-specific DNA binding. p.Pro95fs falls in the disordered region.


### Pathways affected {#pathways}

HAND2 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cardiogenesis](https://reactome.org/content/detail/R-HSA-9733709) | other |
| [Transcriptional regulation by RUNX2](https://reactome.org/content/detail/R-HSA-8878166) | other |

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

**Molecular function:** RNA polymerase II transcription regulatory region sequence-specific DNA binding, DNA-binding transcription activator activity, RNA polymerase II-specific, minor groove of adenine-thymine-rich DNA binding, E-box binding, sequence-specific double-stranded DNA binding.

**Biological process:** adult heart development, positive regulation of cardiac muscle hypertrophy, positive regulation of gene expression, negative regulation of gene expression, regulation of tissue remodeling, positive regulation of transcription by RNA polymerase II.

## Clinical significance {#significance}

**Uncertain significance** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2024-03-04.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | no assertion criteria provided | clinical testing | 2024-03-04 |

## Associated conditions {#conditions}

[HAND2-related disorder](https://sugi.bio/atlas/disease/hand2-related-disorder/).

**Reported phenotype names (ClinVar):** HAND2-related disorder, HAND2-related condition.

## Similar variants {#similar}

Related HAND2 variant pages (same residue, condition, or type): [HAND2 p.Pro95Ala](/variant/hand2-p-pro95ala), [HAND2 p.Pro95Leu](/variant/hand2-p-pro95leu), [HAND2 p.Glu38Gln](/variant/hand2-p-glu38gln), [HAND2 p.Pro8Ser](/variant/hand2-p-pro8ser), [HAND2 p.Val83Leu](/variant/hand2-p-val83leu), [HAND2 p.Glu108=](/variant/hand2-p-glu108), [HAND2 p.Pro84=](/variant/hand2-p-pro84), [HAND2 p.Ala24_Ala32del](/variant/hand2-p-ala24-ala32del).

### 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 3353539). 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.*