Is GMPPA p.Ala115= (c.345T>C) pathogenic?

GMPPA p.Ala115= (c.345T>C) is classified Likely benign in GMPPA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-07-16). Ultra-rare (popmax 0.036%, afr); Associated with alacrima, achalasia, and intellectual disability syndrome.

What condition is associated with GMPPA p.Ala115= (c.345T>C)?

GMPPA p.Ala115= (c.345T>C) is associated with alacrima, achalasia, and intellectual disability syndrome (ClinVar).

How common is GMPPA p.Ala115= (c.345T>C) in the general population?

GMPPA p.Ala115= (c.345T>C) is ultra-rare (popmax 0.036%, afr) (gnomAD).

GMPPA p.Ala115=

c.345T>C · rs761791232 · VCV382996

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.036%, afr)

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 -4.2	GERP -1.8
Overall
CADD	7.444	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.036% African / African-American · 27/74,936 alleles

Filtering AF 0.0254% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0219%

Overall 0.00192% 31/1,614,034 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.036%	2,775
South Asian	0.0022%	45,543
Admixed American	0.00167%	60,010
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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.Ala115=
Coding: c.345T>C
dbSNP: rs761791232
Type: single nucleotide variant
Location: chr2:219501953 (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-ala115 (accessed [today's date]).

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