Is NAGA p.Arg287Cys (c.859C>T) pathogenic?

NAGA p.Arg287Cys (c.859C>T) is classified Uncertain significance in NAGA (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). AlphaMissense: ambiguous (0.4274); Very rare (popmax 0.00668%, eas); Associated with alpha-N-acetylgalactosaminidase deficiency type 2.

What condition is associated with NAGA p.Arg287Cys (c.859C>T)?

NAGA p.Arg287Cys (c.859C>T) is associated with alpha-N-acetylgalactosaminidase deficiency type 2, alpha-N-acetylgalactosaminidase deficiency type 1 (ClinVar).

How common is NAGA p.Arg287Cys (c.859C>T) in the general population?

NAGA p.Arg287Cys (c.859C>T) is very rare (popmax 0.00668%, eas) (gnomAD).

How is Alpha-N-acetylgalactosaminidase deficiency inherited?

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

What do computational predictors say about NAGA p.Arg287Cys (c.859C>T)?

AlphaMissense predicts ambiguous (score 0.4274) — an in-silico prediction, not a clinical call.

NAGA p.Arg287Cys

c.859C>T · rs368220690 · VCV341907

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4274 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

alpha-N-acetylgalactosaminidase deficiency type 2

Computational evidence

Protein change
AlphaMissense	0.4274	ambiguous
REVEL	0.901	moderately pathogenic-leaning
SaProt	LLR -14.05	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 10 kb · p 0.027 · regional, not allelic
Overall
CADD	33.0	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 0.00668% East Asian · 3/44,894 alleles

Filtering AF 0.00207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00242% 39/1,614,044 alleles · very rare exomes 35/1,461,866 · genomes 4/152,178 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,965
European (non-Finnish)	0.00288%	34,707
African / African-American	0.00133%	74,914
South Asian	0.0011%	91,086

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.Arg287Cys
Coding: c.859C>T
MANE Select: NM_000262
dbSNP: rs368220690
Type: single nucleotide variant
Location: chr22:42062925 (GRCh38)
Gene constraint: LOEUF 1.121 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.18 · 7 PDB
Residue 287: a turn

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

Disease context

alpha-N-acetylgalactosaminidase deficiency type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: alpha-N-acetylgalactosaminidase deficiency type 1

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-arg287cys (accessed [today's date]).

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