Is GMPS p.Phe593Ser (c.1778T>C) pathogenic?

GMPS p.Phe593Ser (c.1778T>C) is classified Uncertain significance in GMPS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-22). AlphaMissense: ambiguous (0.3902); Ultra-rare (popmax 0.0172%, nfe).

How common is GMPS p.Phe593Ser (c.1778T>C) in the general population?

GMPS p.Phe593Ser (c.1778T>C) is ultra-rare (popmax 0.0172%, nfe) (gnomAD).

What do computational predictors say about GMPS p.Phe593Ser (c.1778T>C)?

AlphaMissense predicts ambiguous (score 0.3902) — an in-silico prediction, not a clinical call.

GMPS p.Phe593Ser

c.1778T>C · rs777424999 · VCV3100536

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3902 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0172%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3902	ambiguous
REVEL	0.146	moderately benign-leaning
SaProt	LLR -7.20	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.43	unconstrained · MANE · 5,812 bp · p 8.2e-14 · regional, not allelic
Overall
CADD	22.3	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 0.0172% European (non-Finnish) · 202/1,175,306 alleles

Filtering AF 0.0152% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0144%

Overall 0.0129% 208/1,608,862 alleles · ultra-rare exomes 200/1,456,660 · genomes 8/152,202 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0172%	5,818
Remaining individualsnot grpmax-eligible	0.00803%	12,460
African / African-American	0.00134%	74,834

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: GMPS
Protein: p.Phe593Ser
Coding: c.1778T>C
MANE Select: NM_003875
dbSNP: rs777424999
Type: single nucleotide variant
Location: chr3:155935017 (GRCh38)
Gene constraint: LOEUF 1.329 · pLI 0.09 (gnomAD)
Structure: AlphaFold pLDDT 87.06 · 2 PDB
Residue 593: an α-helix

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

Similar variants

GMPS p.Phe593= Benign ★★ same residue
GMPS c.209+5A>G Benign ★★ same type
GMPS p.Thr236= Benign ★★ same type
GMPS p.Tyr528Ser Benign ★★ ⚠ same type
GMPS p.Ala175Glu Uncertain significance ★ ⚠ same type
GMPS p.Ala488Thr Uncertain significance ★ ⚠ same type
GMPS p.Ala605Val Uncertain significance ★ ⚠ same type
GMPS p.Arg169Cys 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/gmps-p-phe593ser (accessed [today's date]).

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