Is AGL p.Pro1067Ser (c.3199C>T) pathogenic?

AGL p.Pro1067Ser (c.3199C>T) is classified Benign in AGL (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.2204); Common (popmax 23%, mid) — too common for a highly-penetrant pathogenic allele; Associated with glycogen storage disease III.

What condition is associated with AGL p.Pro1067Ser (c.3199C>T)?

AGL p.Pro1067Ser (c.3199C>T) is associated with glycogen storage disease III (ClinVar).

What do computational predictors say about AGL p.Pro1067Ser (c.3199C>T)?

AlphaMissense predicts likely benign (score 0.2204) — an in-silico prediction, not a clinical call.

AGL p.Pro1067Ser

Q: How common is AGL p.Pro1067Ser (c.3199C>T) in the general population?

AGL p.Pro1067Ser (c.3199C>T) is common (popmax 23%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

Q: How is Glycogen storage disease due to glycogen debranching enzyme deficiency inherited?

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

c.3199C>T · rs3753494 · VCV256734

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.2204 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 23%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

glycogen storage disease III

Computational evidence

Protein change
AlphaMissense	0.2204	likely benign
REVEL	0.295	indeterminate
SaProt	LLR -9.25	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.6, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 71 kb · p 0.78 · regional, not allelic
Overall
CADD	22.6	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 23% Middle Eastern · 1,394/6,056 alleles

Filtering AF 22% ClinGen BA1/BS1 input FAF95, joint · FAF99 21.6%

Overall 14% 225,966/1,612,830 alleles · common

Ancestry group	Frequency	1 in
Middle Easterngrpmax	23%	4
Amishnot grpmax-eligible	22.1%	5
Ashkenazi Jewishnot grpmax-eligible	18.5%	5
Finnishnot grpmax-eligible	16.9%	6
South Asian	14.4%	7
European (non-Finnish)	14.4%	7
Remaining individualsnot grpmax-eligible	14%	7
African / African-American	12%	8
Admixed American	11%	9
East Asian	2.99%	33

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: AGL
Protein: p.Pro1067Ser
Coding: c.3199C>T
MANE Select: NM_000642
dbSNP: rs3753494
Type: single nucleotide variant
Location: chr1:99892547 (GRCh38)
Gene constraint: LOEUF 0.72 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.88 · 1 PDB
Residue 1067: a UniProt-annotated variant site (in); the 'amylo-1,6-glucosidase' region

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

Disease context

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

For Glycogen storage disease due to glycogen debranching enzyme deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy
Prevalence: 1-9 / 100 000 (United States)

Similar variants

AGL p.Pro1067Ala Uncertain significance ★ ⚠ same residue
AGL p.Pro1067Leu Uncertain significance ⚠ same residue
AGL c.1283+2T>C Likely pathogenic ★★ same condition
AGL c.1284-1G>A Likely pathogenic ★★ same condition
AGL c.1284-2A>G Likely pathogenic ★★ same condition
AGL c.1423+1G>A Pathogenic ★★ same condition
AGL c.1423+1G>C Pathogenic ★★ same condition
AGL c.1423+1G>T Pathogenic/Likely 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/agl-p-pro1067ser (accessed [today's date]).

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