Is GMPPA p.Ile307= (c.921C>T) pathogenic?

GMPPA p.Ile307= (c.921C>T) is classified Likely benign in GMPPA (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-27). Ultra-rare (popmax 0.0539%, nfe); Associated with alacrima, achalasia, and intellectual disability syndrome.

What condition is associated with GMPPA p.Ile307= (c.921C>T)?

GMPPA p.Ile307= (c.921C>T) is associated with alacrima, achalasia, and intellectual disability syndrome (ClinVar).

How common is GMPPA p.Ile307= (c.921C>T) in the general population?

GMPPA p.Ile307= (c.921C>T) is ultra-rare (popmax 0.0539%, nfe) (gnomAD).

GMPPA p.Ile307=

c.921C>T · rs145170112 · VCV507802

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0539%, nfe)

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 -7.2	GERP -2.3
Overall
CADD	0.788	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0539% European (non-Finnish) · 628/1,165,474 alleles

Filtering AF 0.0504% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.049%

Overall 0.0418% 664/1,589,138 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0539%	1,856
Remaining individualsnot grpmax-eligible	0.0424%	2,360
African / African-American	0.0108%	9,302
Admixed American	0.00175%	57,028
South Asian	0.00113%	88,302

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.Ile307=
Coding: c.921C>T
dbSNP: rs145170112
Type: single nucleotide variant
Location: chr2:219506000 (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-ile307 (accessed [today's date]).

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