Is GAA p.Leu751Pro (c.2252T>C) pathogenic?

GAA p.Leu751Pro (c.2252T>C) is classified Uncertain significance in GAA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-10). AlphaMissense: likely pathogenic (0.971); Very rare (popmax 0.00167%, amr).

How common is GAA p.Leu751Pro (c.2252T>C) in the general population?

GAA p.Leu751Pro (c.2252T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about GAA p.Leu751Pro (c.2252T>C)?

AlphaMissense predicts likely pathogenic (score 0.971) — an in-silico prediction, not a clinical call.

GAA p.Leu751Pro

c.2252T>C · VCV4937371

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.971 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.971	likely pathogenic · top 3% in GAA
REVEL	0.981	strongly pathogenic-leaning
SaProt	LLR -16.98	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 1.9, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 15 kb · p 0.22 · regional, not allelic
Overall
CADD	29.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,000 alleles

Overall 6.2e-05% 1/1,613,422 alleles · very rare exomes 0/1,461,260 · genomes 1/152,162 · joint denominator

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: GAA
Protein: p.Leu751Pro
Coding: c.2252T>C
MANE Select: NM_000152
Type: single nucleotide variant
Location: chr17:80117030 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.32 · 19 PDB
Residue 751: a β-strand

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

Similar variants

GAA p.Leu751= Conflicting classifications of pathogenicity ★ same residue
GAA c.1076-1G>C Pathogenic ★★★ same type
GAA c.1076-22T>G Pathogenic ★★★ same type
GAA c.1194+5G>A Likely pathogenic ★★★ same type
GAA c.1326+1G>A Pathogenic ★★★ same type
GAA c.1327-2A>G Pathogenic ★★★ same type
GAA c.1437+1G>A Likely pathogenic ★★★ same type
GAA c.1437+2T>C Pathogenic ★★★ 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/gaa-p-leu751pro (accessed [today's date]).

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