Is NUS1 p.Pro112Arg (c.335C>G) pathogenic?

NUS1 p.Pro112Arg (c.335C>G) is classified Uncertain significance in NUS1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-06-10). AlphaMissense: likely benign (0.2004); Very rare (popmax 0.00061%, nfe); Associated with congenital disorder of glycosylation, type Iaa.

What condition is associated with NUS1 p.Pro112Arg (c.335C>G)?

NUS1 p.Pro112Arg (c.335C>G) is associated with congenital disorder of glycosylation, type Iaa (ClinVar).

How common is NUS1 p.Pro112Arg (c.335C>G) in the general population?

NUS1 p.Pro112Arg (c.335C>G) is very rare (popmax 0.00061%, nfe) (gnomAD).

What do computational predictors say about NUS1 p.Pro112Arg (c.335C>G)?

AlphaMissense predicts likely benign (score 0.2004) — an in-silico prediction, not a clinical call.

NUS1 p.Pro112Arg

c.335C>G · rs540846579 · VCV1446856

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2004 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00061%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital disorder of glycosylation, type Iaa

Computational evidence

Protein change
AlphaMissense	0.2004	likely benign
REVEL	0.103	moderately benign-leaning
SaProt	LLR -10.77	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP 2.8, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 18 kb · p 0.003 · regional, not allelic
Overall
CADD	20.4	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 0.00061% European (non-Finnish) · 7/1,146,904 alleles

Filtering AF 0.000254% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000163%

Overall 0.000452% 7/1,549,646 alleles · very rare exomes 7/1,397,402 · genomes 0/152,244 · joint denominator

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: NUS1
Protein: p.Pro112Arg
Coding: c.335C>G
MANE Select: NM_138459
dbSNP: rs540846579
Type: single nucleotide variant
Location: chr6:117676005 (GRCh38)
Gene constraint: LOEUF 0.182 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 82.01 · 9 PDB
Residue 112: a UniProt-annotated variant site (found in a patient with progressive myoclonus epilepsy; likely pathogenic)

Full NUS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Similar variants

NUS1 p.Pro112= Likely benign ★ same residue
NUS1 c.415+1G>A Pathogenic/Likely pathogenic ★★ same condition
NUS1 c.692-2A>G Likely pathogenic ★★ same condition
NUS1 p.Arg290Cys Pathogenic/Likely pathogenic ★★ same condition
NUS1 p.Leu240Ter Pathogenic/Likely pathogenic ★★ same condition
NUS1 p.Ala44Thr Uncertain significance ★★ ⚠ same condition
NUS1 p.Ala79Val Uncertain significance ★★ ⚠ same condition
NUS1 p.Arg10Trp 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/nus1-p-pro112arg (accessed [today's date]).

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