# NM_003977.4(AIP):c.571C>T (p.Arg191Cys)

https://sugi.bio/variant/aip-p-arg191cys

## Summary

**AIP p.Arg191Cys (c.571C>T)** is classified **Conflicting classifications of pathogenicity** in AIP (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.2098); Ultra-rare (popmax 0.049%, eas); Associated with hereditary neoplastic syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs189861025 · 5 submitters · 2 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.049%, eas)

## 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 5 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.Arg191Cys |
| Coding change (HGVS c.) | c.571C>T |
| MANE Select transcript | [NM_017900](https://www.ncbi.nlm.nih.gov/nuccore/NM_017900) (variant reported on NM_003977) |
| dbSNP | [rs189861025](https://www.ncbi.nlm.nih.gov/snp/rs189861025/) |
| Variant type | single nucleotide variant |
| Location | chr11:67490140-67490140 (GRCh38) |
| ClinVar | [VCV825923](https://www.ncbi.nlm.nih.gov/clinvar/variation/825923/) |

**All HGVS expressions:** `LRG_460:g.12107C>T`, `LRG_460t1:c.571C>T`, `NC_000011.10:g.67490140C>T`, `NC_000011.9:g.67257611C>T`, `NG_008969.1:g.12107C>T`, `NM_001302959.2:c.394C>T`, `NM_001302960.2:c.571C>T`, `NM_003977.4:c.571C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2098)
- REVEL 0.55 (indeterminate)
- SaProt LLR -10.462 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL makes no call
- Conservation: phyloP 3.927, GERP -0.571, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 28.8**. 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 **0.049%** (eas) · FAF95 0.0331% · FAF99 0.0279% · 22/44,890 in the highest group · 29/1,613,360 alleles overall — ultra-rare (popmax 0.049%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.049% | 2,040 |
| African / African-American | 0.00267% | 37,520 |
| South Asian | 0.0022% | 45,538 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,500 |
| European (non-Finnish) | 0.000169% | 589,998 |

*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 2026-02-03.

**Submitter consensus:** conflicting (3 Uncertain significance, 1 Likely benign, 1 Benign).

**Submission history:** 5 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-09-27 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Baylor Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-03-28 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-05-10 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-02-03 |

## 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, Neoplastic Syndromes, Hereditary, Tumor predisposition, Hereditary neoplastic syndrome, Hereditary Cancer Syndrome, none provided, Pituitary adenoma, growth hormone-secreting, Pituitary tumor, growth hormone-secreting, somatic.

## Similar variants {#similar}

Related AIP variant pages (same residue, condition, or type): [AIP p.Arg191His](/variant/aip-p-arg191his), [AIP p.Arg191Leu](/variant/aip-p-arg191leu), [AIP p.Arg191=](/variant/aip-p-arg191), [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).

### 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 825923). 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.*