Is ABHD12 p.Val68Ala (c.203T>C) pathogenic?

ABHD12 p.Val68Ala (c.203T>C) is classified Conflicting classifications of pathogenicity in ABHD12 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2024-11-06). AlphaMissense: likely benign (0.102); Ultra-rare (popmax 0.0552%, nfe); Associated with PHARC syndrome.

What condition is associated with ABHD12 p.Val68Ala (c.203T>C)?

ABHD12 p.Val68Ala (c.203T>C) is associated with PHARC syndrome, inherited retinal dystrophy (ClinVar).

How common is ABHD12 p.Val68Ala (c.203T>C) in the general population?

ABHD12 p.Val68Ala (c.203T>C) is ultra-rare (popmax 0.0552%, nfe) (gnomAD).

What do computational predictors say about ABHD12 p.Val68Ala (c.203T>C)?

AlphaMissense predicts likely benign (score 0.102) — an in-silico prediction, not a clinical call.

ABHD12 p.Val68Ala

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.203T>C · rs140967031 · VCV337997

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.102 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0552%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PHARC syndrome

Computational evidence

Protein change
AlphaMissense	0.102	likely benign
REVEL	0.057	moderately benign-leaning
SaProt	LLR -6.82	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.4	GERP 2.4, phastCons 0.96
Regional constraint	o/e 1.00	unconstrained · MANE · 90 kb · p 0.94 · regional, not allelic
Overall
CADD	20.6	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 0.0552% European (non-Finnish) · 651/1,180,010 alleles

Filtering AF 0.0516% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0502%

Overall 0.0426% 688/1,614,132 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0552%	1,813
Remaining individualsnot grpmax-eligible	0.0336%	2,977
Admixed American	0.0167%	6,002
African / African-American	0.008%	12,507

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.Val68Ala
Coding: c.203T>C
MANE Select: NM_001042472
dbSNP: rs140967031
Type: single nucleotide variant
Location: chr20:25339340 (GRCh38)
Gene constraint: LOEUF 0.967 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.60
Residue 68: a UniProt-annotated variant site (in pharc)

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: inherited retinal dystrophy

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

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

ABHD12 p.Val68Met Benign ★★ same residue
ABHD12 p.Val68= 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
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-val68ala (accessed [today's date]).

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