# NM_003977.4(AIP):c.784G>C (p.Asp262His)

https://sugi.bio/variant/aip-p-asp262his

## Summary

**AIP p.Asp262His (c.784G>C)** is classified **Uncertain significance** in AIP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-14). AlphaMissense: likely benign (0.1299); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

**At a glance:** Uncertain significance · review: Multiple submitters · 2 submitters · 1 linked condition · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the AIP gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to hereditary neoplastic 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.*

|  |  |
| --- | --- |
| Clinical trials | 31 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019921/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [AIP](https://sugi.bio/atlas/gene/AIP/) |
| Protein change (HGVS p.) | p.Asp262His |
| Coding change (HGVS c.) | c.784G>C |
| MANE Select transcript | [NM_017900](https://www.ncbi.nlm.nih.gov/nuccore/NM_017900) (variant reported on NM_003977) |
| Variant type | single nucleotide variant |
| Location | chr11:67490454-67490454 (GRCh38) |
| ClinVar | [VCV3692359](https://www.ncbi.nlm.nih.gov/clinvar/variation/3692359/) |

**All HGVS expressions:** `LRG_460:g.12421G>C`, `LRG_460t1:c.784G>C`, `NC_000011.10:g.67490454G>C`, `NC_000011.9:g.67257925G>C`, `NG_008969.1:g.12421G>C`, `NM_001302959.2:c.607G>C`, `NM_001302960.2:c.779+5G>C`, `NM_003977.4:c.784G>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1299)
- REVEL 0.469 (indeterminate)
- SaProt LLR -7.103 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- SpliceAI predicts **donor loss** (Δ 0.70) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 11.779, GERP 1.81, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 22.8**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.70**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 5 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- 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.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 70.14, 38% of residues very-high.

**81 experimental structure(s)** (PDB): [3J9M](https://www.rcsb.org/structure/3J9M), [6NU2](https://www.rcsb.org/structure/6NU2), [6NU3](https://www.rcsb.org/structure/6NU3), [6RW4](https://www.rcsb.org/structure/6RW4), [6RW5](https://www.rcsb.org/structure/6RW5), [6VLZ](https://www.rcsb.org/structure/6VLZ).

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

*Describes the biological roles of AIP (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.*


### Pathways affected {#pathways}

AIP participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Mitochondrial ribosome-associated quality control](https://reactome.org/content/detail/R-HSA-9937383) | curated |
| [Mitochondrial translation termination](https://reactome.org/content/detail/R-HSA-5419276) | curated |
| [Mitochondrial translation elongation](https://reactome.org/content/detail/R-HSA-5389840) | electronic |
| [Mitochondrial translation initiation](https://reactome.org/content/detail/R-HSA-5368286) | electronic |

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

**Biological process:** positive regulation of proteolysis.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-06-14.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-09-03 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-06-14 |

## Associated conditions {#conditions}

[hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, not provided, Tumor predisposition, Neoplastic Syndromes, Hereditary, Hereditary Cancer Syndrome, Hereditary neoplastic syndrome, none provided.

## Similar variants {#similar}

Related AIP variant pages (same residue, condition, or type): [AIP p.Asp262Asn](/variant/aip-p-asp262asn), [AIP p.Asp262Glu](/variant/aip-p-asp262glu), [AIP p.Asp262=](/variant/aip-p-asp262), [AIP p.Asp262Gly](/variant/aip-p-asp262gly), [AIP p.Asp262Val](/variant/aip-p-asp262val), [AIP p.Asp262Tyr](/variant/aip-p-asp262tyr), [AIP p.Arg271Trp](/variant/aip-p-arg271trp), [AIP p.Arg304Ter](/variant/aip-p-arg304ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2026-07-14); 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 3692359). 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.*