Is ABHD12 p.Ala348= (c.1044C>T) pathogenic?

ABHD12 p.Ala348= (c.1044C>T) is classified Conflicting classifications of pathogenicity in ABHD12 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-11-01). Ultra-rare (popmax 0.0454%, afr); Associated with PHARC syndrome.

What condition is associated with ABHD12 p.Ala348= (c.1044C>T)?

ABHD12 p.Ala348= (c.1044C>T) is associated with PHARC syndrome (ClinVar).

How common is ABHD12 p.Ala348= (c.1044C>T) in the general population?

ABHD12 p.Ala348= (c.1044C>T) is ultra-rare (popmax 0.0454%, afr) (gnomAD).

ABHD12 p.Ala348=

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.1044C>T · rs371418239 · VCV895669

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0454%, afr)

Conditions

PHARC syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.3	GERP -4.5
Overall
CADD	1.614	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0454% African / African-American · 34/74,902 alleles

Filtering AF 0.0334% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0292%

Overall 0.0104% 167/1,613,326 alleles · ultra-rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.11%	912
African / African-Americangrpmax	0.0454%	2,203
South Asian	0.0253%	3,958
European (non-Finnish)	0.00864%	11,568
East Asian	0.00668%	14,965
Remaining individualsnot grpmax-eligible	0.00641%	15,607

Amish shows a higher raw frequency than the grpmax group above it. 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.

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.Ala348=
Coding: c.1044C>T
MANE Select: NM_001042472
dbSNP: rs371418239
Type: single nucleotide variant
Location: chr20:25302332 (GRCh38)
Gene constraint: LOEUF 0.967 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.60
Residue 348: 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

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

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

ABHD12 p.Ala348Thr Uncertain significance ★★ ⚠ same residue
ABHD12 p.Ala348Val Uncertain significance ★★ ⚠ 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
ABHD12 p.Arg218Gln 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-ala348 (accessed [today's date]).

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