Is NAGA p.Pro197= (c.591C>G) pathogenic?

NAGA p.Pro197= (c.591C>G) is classified Likely benign in NAGA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-30). Very rare (popmax 0.00268%, afr); Associated with alpha-N-acetylgalactosaminidase deficiency type 1.

What condition is associated with NAGA p.Pro197= (c.591C>G)?

NAGA p.Pro197= (c.591C>G) is associated with alpha-N-acetylgalactosaminidase deficiency type 1 (ClinVar).

How common is NAGA p.Pro197= (c.591C>G) in the general population?

NAGA p.Pro197= (c.591C>G) is very rare (popmax 0.00268%, afr) (gnomAD).

How is Alpha-N-acetylgalactosaminidase deficiency inherited?

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

NAGA p.Pro197=

c.591C>G · rs760412026 · VCV2908890

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00268%, afr)

Conditions

alpha-N-acetylgalactosaminidase deficiency type 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.146	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.096	GERP -2.1, phastCons 0.11
Overall
CADD	0.684	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00268% African / African-American · 2/74,718 alleles

Filtering AF 0.000444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.0005% 8/1,598,826 alleles · very rare exomes 5/1,446,590 · genomes 3/152,236 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00268%	37,359
East Asian	0.00226%	44,240
European (non-Finnish)	0.000426%	234,618

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: NAGA
Protein: p.Pro197=
Coding: c.591C>G
MANE Select: NM_000262
dbSNP: rs760412026
Type: single nucleotide variant
Location: chr22:42066716 (GRCh38)
Gene constraint: LOEUF 1.121 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.18 · 7 PDB
Residue 197: a turn

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

Disease context

alpha-N-acetylgalactosaminidase deficiency type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Alpha-N-acetylgalactosaminidase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Adult, Childhood, Infancy

Similar variants

NAGA p.Gln292Ter Pathogenic ★★ same condition
NAGA p.Trp148Ter Pathogenic/Likely pathogenic ★★ same condition
NAGA p.Ala268Thr Uncertain significance ★★ ⚠ same condition
NAGA p.Ala291Thr Uncertain significance ★★ ⚠ same condition
NAGA p.Arg165Trp Uncertain significance ★★ ⚠ same condition
NAGA p.Arg213His Uncertain significance ★★ ⚠ same condition
NAGA p.Arg37His Uncertain significance ★★ ⚠ same condition
NAGA p.Asn391Ser Uncertain significance ★★ ⚠ 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/naga-p-pro197 (accessed [today's date]).

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