Is GMPPA p.Ser298Leu (c.893C>T) pathogenic?

GMPPA p.Ser298Leu (c.893C>T) is classified Uncertain significance in GMPPA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-10). AlphaMissense: likely benign (0.1856); Ultra-rare (popmax 0.0105%, nfe); Associated with Inborn genetic diseases.

What condition is associated with GMPPA p.Ser298Leu (c.893C>T)?

GMPPA p.Ser298Leu (c.893C>T) is associated with Inborn genetic diseases (ClinVar).

How common is GMPPA p.Ser298Leu (c.893C>T) in the general population?

GMPPA p.Ser298Leu (c.893C>T) is ultra-rare (popmax 0.0105%, nfe) (gnomAD).

What do computational predictors say about GMPPA p.Ser298Leu (c.893C>T)?

AlphaMissense predicts likely benign (score 0.1856) — an in-silico prediction, not a clinical call.

GMPPA p.Ser298Leu

c.893C>T · rs761012765 · VCV2344489

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1856 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0105%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.1856	likely benign
REVEL	0.424	indeterminate
SaProt	LLR -12.99	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.6	GERP 1.2, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 6,819 bp · p 0.00018 · regional, not allelic
Overall
CADD	27.1	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 0.0105% European (non-Finnish) · 124/1,177,548 alleles

Filtering AF 0.00893% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00844%

Overall 0.00834% 134/1,606,616 alleles · ultra-rare exomes 125/1,454,406 · genomes 9/152,210 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0105%	9,496
Remaining individualsnot grpmax-eligible	0.00802%	12,464
African / African-American	0.00534%	18,720
South Asian	0.0011%	90,780

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: GMPPA
Protein: p.Ser298Leu
Coding: c.893C>T
MANE Select: NM_013335
dbSNP: rs761012765
Type: single nucleotide variant
Location: chr2:219505754 (GRCh38)

Full GMPPA 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

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/gmppa-p-ser298leu (accessed [today's date]).

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