Is ABHD12 p.Lys99Arg (c.296A>G) pathogenic?

ABHD12 p.Lys99Arg (c.296A>G) is classified Uncertain significance in ABHD12 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-05). AlphaMissense: likely benign (0.1059); Very rare (popmax 0.00223%, eas).

How common is ABHD12 p.Lys99Arg (c.296A>G) in the general population?

ABHD12 p.Lys99Arg (c.296A>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ABHD12 p.Lys99Arg (c.296A>G)?

AlphaMissense predicts likely benign (score 0.1059) — an in-silico prediction, not a clinical call.

ABHD12 p.Lys99Arg

c.296A>G · rs1378903431 · VCV1025439

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1059 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1059	likely benign
REVEL	0.118	moderately benign-leaning
SaProt	LLR -9.15	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 7.8	GERP 2.5, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 90 kb · p 0.94 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,880 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000274% 4/1,461,874 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,880
European (non-Finnish)	0.000254%	393,340

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.Lys99Arg
Coding: c.296A>G
MANE Select: NM_001042472
dbSNP: rs1378903431
Type: single nucleotide variant
Location: chr20:25339247 (GRCh38)
Gene constraint: LOEUF 0.967 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 85.60
Residue 99: a UniProt-annotated variant site (in pharc)

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

Similar variants

ABHD12 c.1029+1G>T Likely pathogenic ★★ same type
ABHD12 p.Arg262Ter Pathogenic ★★ same type
ABHD12 p.Arg292Ter Pathogenic/Likely pathogenic ★★ same type
ABHD12 p.Arg352Ter Pathogenic ★★ same type
ABHD12 p.Arg355Ter Pathogenic ★★ same type
ABHD12 c.620-3C>T Uncertain significance ★★ same type
ABHD12 c.867+2C>T Uncertain significance ★★ same type
ABHD12 p.Ala152Thr Uncertain significance ★★ ⚠ same type

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-lys99arg (accessed [today's date]).

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