Is NGLY1 p.Pro67Arg (c.200C>G) pathogenic?

NGLY1 p.Pro67Arg (c.200C>G) is classified Uncertain significance in NGLY1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-15). AlphaMissense: likely pathogenic (0.9219); Absent from gnomAD v4.1; Associated with congenital disorder of deglycosylation.

What condition is associated with NGLY1 p.Pro67Arg (c.200C>G)?

NGLY1 p.Pro67Arg (c.200C>G) is associated with congenital disorder of deglycosylation (ClinVar).

How common is NGLY1 p.Pro67Arg (c.200C>G) in the general population?

NGLY1 p.Pro67Arg (c.200C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NGLY1 p.Pro67Arg (c.200C>G)?

AlphaMissense predicts likely pathogenic (score 0.9219) — an in-silico prediction, not a clinical call.

NGLY1 p.Pro67Arg

c.200C>G · rs145752045 · VCV2106453

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9219 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

congenital disorder of deglycosylation

Computational evidence

Protein change
AlphaMissense	0.9219	likely pathogenic
REVEL	0.597	indeterminate
SaProt	LLR -10.71	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 64 kb · p 0.75 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NGLY1
Protein: p.Pro67Arg
Coding: c.200C>G
MANE Select: NM_018297
dbSNP: rs145752045
Type: single nucleotide variant
Location: chr3:25778620 (GRCh38)
Gene constraint: LOEUF 1.008 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.57 · 2 PDB
Residue 67: the pub domain; a turn

Full NGLY1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital disorder of deglycosylation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NGLY1 p.Pro67Leu Uncertain significance ★ ⚠ same residue
NGLY1 p.Pro67Ser Uncertain significance ★ ⚠ same residue
NGLY1 p.Pro67= Likely benign ★ same residue
NGLY1 c.1150-1G>C Pathogenic/Likely pathogenic ★★ same condition
NGLY1 c.658+1G>A Likely pathogenic ★★ same condition
NGLY1 p.Arg291Ter Pathogenic/Likely pathogenic ★★ same condition
NGLY1 p.Arg321Ter Pathogenic/Likely pathogenic ★★ same condition
NGLY1 p.Arg390Ter 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/ngly1-p-pro67arg (accessed [today's date]).

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