Is MGLL p.Pro125Ser (c.373C>T) pathogenic?

MGLL p.Pro125Ser (c.373C>T) is classified Uncertain significance in MGLL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-25). AlphaMissense: ambiguous (0.4083); Very rare (popmax 0.00229%, nfe).

How common is MGLL p.Pro125Ser (c.373C>T) in the general population?

MGLL p.Pro125Ser (c.373C>T) is very rare (popmax 0.00229%, nfe) (gnomAD).

What do computational predictors say about MGLL p.Pro125Ser (c.373C>T)?

AlphaMissense predicts ambiguous (score 0.4083) — an in-silico prediction, not a clinical call.

MGLL p.Pro125Ser

c.373C>T · VCV3395672

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4083 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00229%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4083	ambiguous
REVEL	0.667	pathogenic-leaning
SaProt	LLR -11.03	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 0.3, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 130 kb · p 0.0047 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P115S vs ClinVar P125S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00229% European (non-Finnish) · 27/1,180,056 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.00173% 28/1,614,140 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00229%	43,706
African / African-American	0.00133%	74,936

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: MGLL
Protein: p.Pro125Ser
Coding: c.373C>T
MANE Select: NM_007283
Type: single nucleotide variant
Location: chr3:127722456 (GRCh38)
Gene constraint: LOEUF 0.5 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 94.36 · 30 PDB
Residue 125: an α-helix

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

Similar variants

MGLL p.Ala136Thr Uncertain significance ★ ⚠ same type
MGLL p.Ala174Val Uncertain significance ★ ⚠ same type
MGLL p.Ala233Thr Uncertain significance ★ ⚠ same type
MGLL p.Ala305Thr Uncertain significance ★ ⚠ same type
MGLL p.Arg229Trp Uncertain significance ★ ⚠ same type
MGLL p.Arg232His Uncertain significance ★ ⚠ same type
MGLL p.Arg250Cys Uncertain significance ★ ⚠ same type
MGLL p.Arg73Gly 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/mgll-p-pro125ser (accessed [today's date]).

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