Is GSDME p.Pro142Ala (c.424C>G) pathogenic?

GSDME p.Pro142Ala (c.424C>G) is classified Uncertain significance in GSDME (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-13). AlphaMissense: likely benign (0.0967); Very rare (popmax 0.00915%, nfe); Associated with Inborn genetic diseases.

What condition is associated with GSDME p.Pro142Ala (c.424C>G)?

GSDME p.Pro142Ala (c.424C>G) is associated with Inborn genetic diseases (ClinVar).

How common is GSDME p.Pro142Ala (c.424C>G) in the general population?

GSDME p.Pro142Ala (c.424C>G) is very rare (popmax 0.00915%, nfe) (gnomAD).

What do computational predictors say about GSDME p.Pro142Ala (c.424C>G)?

AlphaMissense predicts likely benign (score 0.0967) — an in-silico prediction, not a clinical call.

GSDME p.Pro142Ala

c.424C>G · rs754554 · VCV1800573

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0967 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00915%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0967	likely benign
REVEL	0.062	moderately benign-leaning
SaProt	LLR -7.79	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5	GERP -0.68, phastCons 1
Regional constraint	o/e 1.10	unconstrained · MANE · 51 kb · p 0.017 · regional, not allelic
Overall
CADD	15.56	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 0.00915% European (non-Finnish) · 108/1,179,792 alleles

Filtering AF 0.00774% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00719%

Overall 0.00763% 123/1,612,144 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00915%	10,924
Admixed American	0.00833%	12,006
African / African-American	0.008%	12,496
Remaining individualsnot grpmax-eligible	0.0064%	15,620

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: GSDME
Protein: p.Pro142Ala
Coding: c.424C>G
MANE Select: NM_001127453
dbSNP: rs754554
Type: single nucleotide variant
Location: chr7:24719199 (GRCh38)
Gene constraint: LOEUF 1.142 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.89 · 4 PDB
Residue 142: a UniProt-annotated variant site (in)

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GSDME p.Pro142Thr Benign ★★ same residue
GSDME p.Pro142= Likely benign ★ same residue
GSDME p.Ala288Glu Uncertain significance ★★ ⚠ same condition
GSDME p.Ala316Val Uncertain significance ★★ ⚠ same condition
GSDME p.Ala343Val Uncertain significance ★★ ⚠ same condition
GSDME p.Arg108Cys Uncertain significance ★★ ⚠ same condition
GSDME p.Arg261Gln Uncertain significance ★★ ⚠ same condition
GSDME p.Arg351Trp 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/gsdme-p-pro142ala (accessed [today's date]).

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