Is GAA p.Ser46Pro (c.136T>C) pathogenic?

GAA p.Ser46Pro (c.136T>C) is classified Likely benign in GAA (ClinVar, Single submitter, 1 submitter; last evaluated 2026-07-01). AlphaMissense: likely benign (0.0664); Very rare (popmax 0.000186%); Associated with glycogen storage disease II.

What condition is associated with GAA p.Ser46Pro (c.136T>C)?

GAA p.Ser46Pro (c.136T>C) is associated with glycogen storage disease II (ClinVar).

How common is GAA p.Ser46Pro (c.136T>C) in the general population?

GAA p.Ser46Pro (c.136T>C) is very rare (popmax 0.000186%) (gnomAD).

What do computational predictors say about GAA p.Ser46Pro (c.136T>C)?

AlphaMissense predicts likely benign (score 0.0664) — an in-silico prediction, not a clinical call.

GAA p.Ser46Pro

Q: How is Glycogen storage disease due to acid maltase deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.136T>C · VCV4876254

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0664 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000186%)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

glycogen storage disease II

Computational evidence

Protein change
AlphaMissense	0.0664	likely benign
REVEL	0.478	indeterminate
SaProt	LLR -6.30	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.36	GERP -2.2
Regional constraint	o/e 1.03	unconstrained · MANE · 15 kb · p 0.22 · regional, not allelic
Overall
CADD	6.695	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000186%

Overall 0.000186% 3/1,611,876 alleles · very rare exomes 3/1,459,730 · genomes 0/152,146 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00319%	31,373
Remaining individualsnot grpmax-eligible	0.0016%	62,384

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: GAA
Protein: p.Ser46Pro
Coding: c.136T>C
MANE Select: NM_000152
Type: single nucleotide variant
Location: chr17:80104722 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.32 · 19 PDB
Residue 46: a UniProt-annotated variant site (in iopd)

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

Disease context

glycogen storage disease II — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Glycogen storage disease due to acid maltase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

GAA p.Ser46= Conflicting classifications of pathogenicity ★ same residue
GAA c.1076-1G>C Pathogenic ★★★ same condition
GAA c.1076-22T>G Pathogenic ★★★ same condition
GAA c.1194+5G>A Likely pathogenic ★★★ same condition
GAA c.1326+1G>A Pathogenic ★★★ same condition
GAA c.1327-2A>G Pathogenic ★★★ same condition
GAA c.1437+1G>A Likely pathogenic ★★★ same condition
GAA c.1437+2T>C Pathogenic ★★★ same condition

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-ser46pro (accessed [today's date]).

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