Is ABHD12 p.Arg186Pro (c.557G>C) pathogenic?

ABHD12 p.Arg186Pro (c.557G>C) is classified Conflicting classifications of pathogenicity in ABHD12 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2016-09-01). AlphaMissense: likely pathogenic (0.9986); Very rare (popmax 8.48e-05%, nfe); Associated with PHARC syndrome.

What condition is associated with ABHD12 p.Arg186Pro (c.557G>C)?

ABHD12 p.Arg186Pro (c.557G>C) is associated with PHARC syndrome, cone dystrophy (ClinVar).

How common is ABHD12 p.Arg186Pro (c.557G>C) in the general population?

ABHD12 p.Arg186Pro (c.557G>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about ABHD12 p.Arg186Pro (c.557G>C)?

AlphaMissense predicts likely pathogenic (score 0.9986) — an in-silico prediction, not a clinical call.

ABHD12 p.Arg186Pro

Q: How is Polyneuropathy-hearing loss-ataxia-retinitis pigmentosa-cataract syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.557G>C · rs587777604 · VCV143237

Conflicting classifications of pathogenicity No assertion criteria

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9986 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PHARC syndrome

Computational evidence

Protein change
AlphaMissense	0.9986	likely pathogenic · top 3% in ABHD12
REVEL	0.829	moderately pathogenic-leaning
SaProt	LLR -15.30	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 90 kb · p 0.94 · regional, not allelic
Overall
CADD	29.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,372 alleles

Overall 6.85e-05% 1/1,460,288 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ABHD12
Protein: p.Arg186Pro
Coding: c.557G>C
MANE Select: NM_001042472
dbSNP: rs587777604
Type: single nucleotide variant
Location: chr20:25317064 (GRCh38)
Gene constraint: LOEUF 0.967 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.60
Residue 186: a UniProt-annotated variant site (in pharc); a UniProt-annotated variant site (in pharc; uncertain significance)

Full ABHD12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

PHARC syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cone dystrophy

For Polyneuropathy-hearing loss-ataxia-retinitis pigmentosa-cataract syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

ABHD12 p.Arg186Cys Uncertain significance ★★ ⚠ same residue
ABHD12 p.Arg186His Uncertain significance ★★ same residue
ABHD12 p.Arg186= Likely benign ★ same residue
ABHD12 p.Arg292Ter Pathogenic/Likely pathogenic ★★ same condition
ABHD12 p.Arg352Ter Pathogenic ★★ same condition
ABHD12 c.867+2C>T Uncertain significance ★★ same condition
ABHD12 p.Ala56Val Uncertain significance ★★ ⚠ same condition
ABHD12 p.Ala9Val Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/abhd12-p-arg186pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown