Is ABHD8 p.Pro374Leu (c.1121C>T) pathogenic?

ABHD8 p.Pro374Leu (c.1121C>T) is classified Uncertain significance in ABHD8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-25). AlphaMissense: likely pathogenic (0.6424); Very rare (popmax 0.00797%, nfe).

How common is ABHD8 p.Pro374Leu (c.1121C>T) in the general population?

ABHD8 p.Pro374Leu (c.1121C>T) is very rare (popmax 0.00797%, nfe) (gnomAD).

What do computational predictors say about ABHD8 p.Pro374Leu (c.1121C>T)?

AlphaMissense predicts likely pathogenic (score 0.6424) — an in-silico prediction, not a clinical call.

ABHD8 p.Pro374Leu

c.1121C>T · rs199521781 · VCV2347125

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6424 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00797%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6424	likely pathogenic
REVEL	0.592	indeterminate
SaProt	LLR -8.68	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 0.61, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 8,424 bp · p 8.1e-06 · regional, not allelic
Overall
CADD	31.0	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 0.00797% European (non-Finnish) · 94/1,179,854 alleles

Filtering AF 0.00664% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00616%

Overall 0.00634% 102/1,608,896 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00797%	12,552
Remaining individualsnot grpmax-eligible	0.00641%	15,601
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,598
African / African-American	0.00267%	37,457
Finnishnot grpmax-eligible	0.00168%	59,524

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.Pro374Leu
Coding: c.1121C>T
MANE Select: NM_024527
dbSNP: rs199521781
Type: single nucleotide variant
Location: chr19:17294316 (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-pro374leu (accessed [today's date]).

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