Is GMPPA p.Ala71= (c.213C>T) pathogenic?

GMPPA p.Ala71= (c.213C>T) is classified Benign/Likely benign in GMPPA (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-26). Low-frequency (popmax 1.56%, nfe); Associated with alacrima, achalasia, and intellectual disability syndrome.

What condition is associated with GMPPA p.Ala71= (c.213C>T)?

GMPPA p.Ala71= (c.213C>T) is associated with alacrima, achalasia, and intellectual disability syndrome (ClinVar).

How common is GMPPA p.Ala71= (c.213C>T) in the general population?

GMPPA p.Ala71= (c.213C>T) is low-frequency (popmax 1.56%, nfe) (gnomAD).

GMPPA p.Ala71=

c.213C>T · rs41272703 · VCV382083

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.56%, nfe)

Conditions

alacrima, achalasia, and intellectual disability syndrome

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

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 -0.8	GERP -2.6, phastCons 0.016
Overall
CADD	5.646	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.56% European (non-Finnish) · 18,330/1,177,566 alleles

Filtering AF 1.54% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.53%

Overall 1.4% 22,529/1,611,450 alleles · low-frequency exomes 20,750/1,459,190 · genomes 1,779/152,260 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	3.68%	27
European (non-Finnish)grpmax	1.56%	64
Ashkenazi Jewishnot grpmax-eligible	1.19%	84
Remaining individualsnot grpmax-eligible	1.11%	90
South Asian	0.499%	200
Admixed American	0.282%	355
African / African-American	0.217%	460
Middle Eastern	0.149%	673
Amishnot grpmax-eligible	0.11%	912

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala71=
Coding: c.213C>T
MANE Select: NM_013335
dbSNP: rs41272703
Type: single nucleotide variant
Location: chr2:219501550 (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-ala71 (accessed [today's date]).

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