# NM_001042472.3(ABHD12):c.858A>C (p.Pro286=)

https://sugi.bio/variant/abhd12-p-pro286

## Summary

**ABHD12 p.Pro286= (c.858A>C)** is classified **Conflicting classifications of pathogenicity** in ABHD12 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-05-28). Very rare (popmax 0.00635%, nfe); Associated with PHARC syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs372807311 · 4 submitters · 1 linked condition · very rare (popmax 0.00635%, nfe)

## For patients & families {#patients}

This is a change in the ABHD12 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 submitters, and is linked to PHARC 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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Childhood |
| Diagnostic panels | ABHD12 is a diagnostic-grade gene on 16 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017071/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ABHD12](https://sugi.bio/atlas/gene/ABHD12/) |
| Protein change (HGVS p.) | p.Pro286= |
| Coding change (HGVS c.) | c.858A>C |
| MANE Select transcript | [NM_001042472](https://www.ncbi.nlm.nih.gov/nuccore/NM_001042472) |
| dbSNP | [rs372807311](https://www.ncbi.nlm.nih.gov/snp/rs372807311/) |
| Variant type | single nucleotide variant |
| Location | chr20:25307975-25307975 (GRCh38) |
| ClinVar | [VCV337991](https://www.ncbi.nlm.nih.gov/clinvar/variation/337991/) |

**All HGVS expressions:** `NC_000020.10:g.25288611T>G`, `NC_000020.11:g.25307975T>G`, `NG_028119.1:g.88008A>C`, `NM_001042472.3:c.858A>C`, `NM_015600.5:c.858A>C`

## 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 -12.443, GERP -4.95 — fast-evolving / accelerated position
- CADD: **PHRED 0.354**. 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 **0.00635%** (nfe) · FAF95 0.00517% · FAF99 0.00474% · 74/1,165,690 in the highest group · 126/1,598,142 alleles overall — very rare (popmax 0.00635%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.136% | 737 |
| Remaining individuals (not grpmax-eligible) | 0.0129% | 7,747 |
| European (non-Finnish) (grpmax) | 0.00635% | 15,753 |
| Admixed American | 0.005% | 19,985 |
| African / African-American | 0.00134% | 74,782 |

Ashkenazi Jewish 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}

**ABHD12** population constraint: LOEUF 0.967, pLI 7.5081e-10, missense-Z -0.50211; ClinGen dosage — haploinsufficiency gene assoc. with recessive phenotype, triplosensitivity Not yet evaluated/3. *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):

- **PHARC syndrome** — Definitive (AR)

## Protein context {#protein}

Residue **286** lies in a UniProt-annotated variant site (in pharc); a UniProt-annotated variant site (in pharc; uncertain significance).

AlphaFold model confidence (whole protein): pLDDT 85.60, 65% of residues very-high.

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

*Describes the biological roles of ABHD12 (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:** ABHD12's established molecular role includes glycerophospholipase activity.


### Pathways affected {#pathways}

ABHD12 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Arachidonate production from DAG](https://reactome.org/content/detail/R-HSA-426048) | curated |

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

**Molecular function:** glycerophospholipase activity, phosphatidylcholine lysophospholipase A1 activity, monoacylglycerol lipase activity, phosphatidylserine lysophospholipase A1 activity.

**Biological process:** phosphatidylserine catabolic process, phospholipid catabolic process, acylglycerol catabolic process, glycerophospholipid catabolic process, monoacylglycerol catabolic process.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-05-28.

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

**Submission history:** 4 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-04-24 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-05-28 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-09-03 |

## Associated conditions {#conditions}

[PHARC syndrome](https://sugi.bio/atlas/disease/pharc-syndrome/).

**Reported phenotype names (ClinVar):** PHARC syndrome, not provided, not specified, none provided, Polyneuropathy-hearing loss-ataxia-retinitis pigmentosa-cataract syndrome, AllHighlyPenetrant.

## Similar variants {#similar}

Related ABHD12 variant pages (same residue, condition, or type): [ABHD12 p.Arg292Ter](/variant/abhd12-p-arg292ter), [ABHD12 p.Arg352Ter](/variant/abhd12-p-arg352ter), [ABHD12 c.867+2C>T](/variant/abhd12-c-867-plus-2c-t), [ABHD12 p.Ala56Val](/variant/abhd12-p-ala56val), [ABHD12 p.Ala9Val](/variant/abhd12-p-ala9val), [ABHD12 p.Arg218Gln](/variant/abhd12-p-arg218gln), [ABHD12 p.Arg279His](/variant/abhd12-p-arg279his), [ABHD12 p.Arg292Gln](/variant/abhd12-p-arg292gln).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 337991). 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.*