# NM_001130111.2(ABHD17A):c.116C>G (p.Pro39Arg)

https://sugi.bio/variant/abhd17a-p-pro39arg

## Summary

**ABHD17A p.Pro39Arg (c.116C>G)** is classified **Uncertain significance** in ABHD17A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-05). AlphaMissense: likely benign (0.1471); Ultra-rare (popmax 0.0451%, mid).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · ultra-rare (popmax 0.0451%, mid)

## For patients & families {#patients}

This is a change in the ABHD17A gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [ABHD17A](https://sugi.bio/atlas/gene/ABHD17A/) |
| Protein change (HGVS p.) | p.Pro39Arg |
| Coding change (HGVS c.) | c.116C>G |
| MANE Select transcript | [NM_001130111](https://www.ncbi.nlm.nih.gov/nuccore/NM_001130111) |
| Variant type | single nucleotide variant |
| Location | chr19:1881451-1881451 (GRCh38) |
| ClinVar | [VCV3992868](https://www.ncbi.nlm.nih.gov/clinvar/variation/3992868/) |

**All HGVS expressions:** `NC_000019.10:g.1881451G>C`, `NC_000019.9:g.1881450G>C`, `NM_001130111.2:c.116C>G`, `NM_031213.4:c.116C>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1471)
- REVEL 0.101 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.051 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **donor gain** (Δ 0.26) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 8.277, GERP -2.87, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 22.4**. 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 0.79** across the covering region of the MANE Select transcript (1,880,001–1,881,566), spanning 1,565 bp. Chi-square p 0.0021. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.06**, donor gain **0.26**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.06**, donor gain **0.26**.
- Pangolin: Δ**0.34** (gain), gain 0.34 / loss 0.00. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0451%** (mid) · FAF95 0.008% · FAF99 0.00335% · 2/4,430 in the highest group · 13/1,603,244 alleles overall — ultra-rare (popmax 0.0451%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0451% | 2,215 |
| Remaining individuals (not grpmax-eligible) | 0.00483% | 20,698 |
| South Asian | 0.0033% | 30,289 |
| European (non-Finnish) | 0.000424% | 235,700 |

*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}

**ABHD17A** population constraint: LOEUF 0.783, pLI 0.21099, missense-Z 1.5027. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 89.99, 82% of residues very-high.

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

*Describes the biological roles of ABHD17A (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:** ABHD17A's established molecular role includes palmitoyl-(protein) hydrolase activity.


### Pathways affected {#pathways}

ABHD17A participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [RAS processing](https://reactome.org/content/detail/R-HSA-9648002) | curated |

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

**Molecular function:** palmitoyl-(protein) hydrolase activity.

**Biological process:** protein depalmitoylation, protein localization to membrane, negative regulation of NLRP3 inflammasome complex assembly.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-05-05.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-05-05 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related ABHD17A variant pages (same residue, condition, or type): [ABHD17A c.332+230G>A](/variant/abhd17a-c-332-plus-230g-a), [ABHD17A c.332+239C>G](/variant/abhd17a-c-332-plus-239c-g), [ABHD17A c.332+243G>A](/variant/abhd17a-c-332-plus-243g-a), [ABHD17A c.332+261C>G](/variant/abhd17a-c-332-plus-261c-g), [ABHD17A c.332+261C>T](/variant/abhd17a-c-332-plus-261c-t), [ABHD17A c.332+306C>T](/variant/abhd17a-c-332-plus-306c-t), [ABHD17A p.Ala168Thr](/variant/abhd17a-p-ala168thr), [ABHD17A p.Ala273Thr](/variant/abhd17a-p-ala273thr).

### 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 3992868). 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.*