# NM_003977.4(AIP):c.301G>A (p.Val101Met)

https://sugi.bio/variant/aip-p-val101met

## Summary

**AIP p.Val101Met (c.301G>A)** is classified **Conflicting classifications of pathogenicity** in AIP (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-12-23). AlphaMissense: likely pathogenic (0.7169); Rare (popmax 0.237%, afr); Associated with hereditary neoplastic syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs147931650 · 7 submitters · 2 linked conditions · AlphaMissense likely pathogenic · rare (popmax 0.237%, afr)

## For patients & families {#patients}

This is a change in the AIP gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 7 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.Val101Met |
| Coding change (HGVS c.) | c.301G>A |
| MANE Select transcript | [NM_017900](https://www.ncbi.nlm.nih.gov/nuccore/NM_017900) (variant reported on NM_003977) |
| dbSNP | [rs147931650](https://www.ncbi.nlm.nih.gov/snp/rs147931650/) |
| Variant type | single nucleotide variant |
| Location | chr11:67489288-67489288 (GRCh38) |
| ClinVar | [VCV305726](https://www.ncbi.nlm.nih.gov/clinvar/variation/305726/) |

**All HGVS expressions:** `LRG_460:g.11255G>A`, `LRG_460t1:c.301G>A`, `NC_000011.10:g.67489288G>A`, `NC_000011.9:g.67256759G>A`, `NG_008969.1:g.11255G>A`, `NM_001302959.2:c.124G>A`, `NM_001302960.2:c.301G>A`, `NM_003977.3:c.301G>A`, `NM_003977.4:c.301G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.7169)
- REVEL 0.805 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -11.296 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 9.909, GERP -3.9, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 29.8**. 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: **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 **0.237%** (afr) · FAF95 0.209% · FAF99 0.198% · 178/74,972 in the highest group · 188/1,611,466 alleles overall — rare (popmax 0.237%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.237% | 421 |
| Admixed American | 0.00834% | 11,994 |
| Remaining individuals (not grpmax-eligible) | 0.00641% | 15,592 |
| European (non-Finnish) | 8.48e-05% | 1,179,743 |

*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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-12-23.

**Submitter consensus:** conflicting (4 Likely benign, 2 Uncertain significance, 1 Benign).

**Submission history:** 7 submissions (2018–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2020-03-17 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-23 |
| Sema4, Sema4 | Likely benign | criteria provided, single submitter | curation | 2020-10-23 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-08-17 |
| Genetic Services Laboratory, University of Chicago | Uncertain significance | no assertion criteria provided | clinical testing | 2022-06-20 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2022-06-28 |

## Associated conditions {#conditions}

[hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [growth hormone secreting pituitary adenoma 1](https://sugi.bio/atlas/disease/growth-hormone-secreting-pituitary-adenoma-1/).

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, Somatotroph adenoma, not provided, not specified, AIP-related disorder, AIP-related condition, Tumor predisposition, Neoplastic Syndromes, Hereditary, Hereditary Cancer Syndrome, Hereditary neoplastic syndrome.

## Same-residue context {#hotspot}

Residue **101** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [AIP p.Val101_Leu141del](/variant/aip-p-val101-leu141del). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related AIP variant pages (same residue, condition, or type): [AIP p.Val101=](/variant/aip-p-val101), [AIP p.Val101_Leu141del](/variant/aip-p-val101-leu141del), [AIP p.Arg271Trp](/variant/aip-p-arg271trp), [AIP p.Arg304Ter](/variant/aip-p-arg304ter), [AIP p.Arg81Ter](/variant/aip-p-arg81ter), [AIP p.Cys238Tyr](/variant/aip-p-cys238tyr), [AIP p.Gln126Ter](/variant/aip-p-gln126ter), [AIP p.Gln14Ter](/variant/aip-p-gln14ter).

### 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 305726). 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.*