Is NAGA p.Arg199= (c.595A>C) pathogenic?

NAGA p.Arg199= (c.595A>C) is classified Likely benign in NAGA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-07). Ultra-rare (popmax 0.0249%, eas); Associated with alpha-N-acetylgalactosaminidase deficiency type 1.

What condition is associated with NAGA p.Arg199= (c.595A>C)?

NAGA p.Arg199= (c.595A>C) is associated with alpha-N-acetylgalactosaminidase deficiency type 1 (ClinVar).

How common is NAGA p.Arg199= (c.595A>C) in the general population?

NAGA p.Arg199= (c.595A>C) is ultra-rare (popmax 0.0249%, eas) (gnomAD).

How is Alpha-N-acetylgalactosaminidase deficiency inherited?

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

NAGA p.Arg199=

c.595A>C · rs371198022 · VCV2903089

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0249%, eas)

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	0.048	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.5	GERP -2.8
Overall
CADD	1.784	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0249% East Asian · 11/44,168 alleles

Filtering AF 0.0139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0107%

Overall 0.00307% 49/1,596,996 alleles · ultra-rare exomes 45/1,444,872 · genomes 4/152,124 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0249%	4,015
European (non-Finnish)	0.00316%	31,682
Remaining individualsnot grpmax-eligible	0.00162%	61,784

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.Arg199=
Coding: c.595A>C
MANE Select: NM_000262
dbSNP: rs371198022
Type: single nucleotide variant
Location: chr22:42066712 (GRCh38)
Gene constraint: LOEUF 1.121 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.18 · 7 PDB
Residue 199: 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-arg199 (accessed [today's date]).

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