Is GMPS p.Phe593= (c.1779T>C) pathogenic?

GMPS p.Phe593= (c.1779T>C) is classified Benign in GMPS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). Common (popmax 6.24%, afr) — too common for a highly-penetrant pathogenic allele.

GMPS p.Phe593=

Q: How common is GMPS p.Phe593= (c.1779T>C) in the general population?

GMPS p.Phe593= (c.1779T>C) is common (popmax 6.24%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1779T>C · rs139844459 · VCV775920

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 6.24%, afr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.48	GERP 0.66, phastCons 1
Overall
CADD	9.901	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.24% African / African-American · 4,674/74,918 alleles

Filtering AF 6.09% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.03%

Overall 0.371% 5,971/1,609,180 alleles · common exomes 3,282/1,456,854 · genomes 2,689/152,326 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	6.24%	16
Middle Eastern	0.562%	178
Remaining individualsnot grpmax-eligible	0.48%	208
Admixed American	0.458%	218
Ashkenazi Jewishnot grpmax-eligible	0.105%	955
European (non-Finnish)	0.0551%	1,814
South Asian	0.011%	9,098

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.Phe593=
Coding: c.1779T>C
MANE Select: NM_003875
dbSNP: rs139844459
Type: single nucleotide variant
Location: chr3:155935018 (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.Phe593Ser Uncertain significance ★ ⚠ 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-phe593 (accessed [today's date]).

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