Is ABHD8 p.Arg100Pro (c.299G>C) pathogenic?

ABHD8 p.Arg100Pro (c.299G>C) is classified Uncertain significance in ABHD8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-12). AlphaMissense: likely benign (0.1098); Ultra-rare (popmax 0.0217%, amr).

How common is ABHD8 p.Arg100Pro (c.299G>C) in the general population?

ABHD8 p.Arg100Pro (c.299G>C) is ultra-rare (popmax 0.0217%, amr) (gnomAD).

What do computational predictors say about ABHD8 p.Arg100Pro (c.299G>C)?

AlphaMissense predicts likely benign (score 0.1098) — an in-silico prediction, not a clinical call.

ABHD8 p.Arg100Pro

c.299G>C · VCV3431836

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1098 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1098	likely benign
REVEL	0.19	benign-leaning
SaProt	LLR -5.08	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 4.6	GERP 0.72, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 527 bp · p 0.13 · regional, not allelic
Overall
CADD	21.2	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 0.0217% Admixed American · 13/59,996 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0101%

Overall 0.00255% 41/1,607,452 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0217%	4,615
Remaining individualsnot grpmax-eligible	0.0144%	6,935
African / African-American	0.00534%	18,732
East Asian	0.00223%	44,876
European (non-Finnish)	0.00119%	84,274

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: ABHD8
Protein: p.Arg100Pro
Coding: c.299G>C
MANE Select: NM_024527
Type: single nucleotide variant
Location: chr19:17301318 (GRCh38)
Gene constraint: LOEUF 0.664 · pLI 0.25 (gnomAD)
Structure: AlphaFold pLDDT 79.84

Full ABHD8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABHD8 p.Ala20= Benign ★★ same type
ABHD8 p.Ala136Thr Uncertain significance ★ ⚠ same type
ABHD8 p.Ala215Val Uncertain significance ★ ⚠ same type
ABHD8 p.Ala218Val Uncertain significance ★ ⚠ same type
ABHD8 p.Ala236Thr Uncertain significance ★ ⚠ same type
ABHD8 p.Ala319Asp Uncertain significance ★ ⚠ same type
ABHD8 p.Ala319Gly Uncertain significance ★ ⚠ same type
ABHD8 p.Ala426Pro 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/abhd8-p-arg100pro (accessed [today's date]).

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