Is GMPPA p.Phe22= (c.66T>C) pathogenic?

GMPPA p.Phe22= (c.66T>C) is classified Likely benign in GMPPA (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-31). Very rare (popmax 6.91e-05%); Associated with alacrima, achalasia, and intellectual disability syndrome.

What condition is associated with GMPPA p.Phe22= (c.66T>C)?

GMPPA p.Phe22= (c.66T>C) is associated with alacrima, achalasia, and intellectual disability syndrome (ClinVar).

How common is GMPPA p.Phe22= (c.66T>C) in the general population?

GMPPA p.Phe22= (c.66T>C) is very rare (popmax 6.91e-05%) (gnomAD).

GMPPA p.Phe22=

c.66T>C · rs1575219520 · VCV745193

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 6.91e-05%)

Conditions

alacrima, achalasia, and intellectual disability syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 1.2	GERP 0.032, phastCons 1
Overall
CADD	12.36	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.91e-05%

Overall 6.91e-05% 1/1,448,126 alleles · very rare

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.Phe22=
Coding: c.66T>C
dbSNP: rs1575219520
Type: single nucleotide variant
Location: chr2:219500146 (GRCh38)

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

Disease context

alacrima, achalasia, and intellectual disability syndrome — 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-phe22 (accessed [today's date]).

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