Is NUS1 p.Pro59Ser (c.175C>T) pathogenic?

NUS1 p.Pro59Ser (c.175C>T) is classified Uncertain significance in NUS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-02-19). AlphaMissense: likely benign (0.087); Very rare (popmax 0.00275%, afr); Associated with congenital disorder of glycosylation, type Iaa.

What condition is associated with NUS1 p.Pro59Ser (c.175C>T)?

NUS1 p.Pro59Ser (c.175C>T) is associated with congenital disorder of glycosylation, type Iaa (ClinVar).

How common is NUS1 p.Pro59Ser (c.175C>T) in the general population?

NUS1 p.Pro59Ser (c.175C>T) is very rare (popmax 0.00275%, afr) (gnomAD).

What do computational predictors say about NUS1 p.Pro59Ser (c.175C>T)?

AlphaMissense predicts likely benign (score 0.087) — an in-silico prediction, not a clinical call.

NUS1 p.Pro59Ser

c.175C>T · rs764639190 · VCV1432469

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.087 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00275%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital disorder of glycosylation, type Iaa

Computational evidence

Protein change
AlphaMissense	0.087	likely benign
REVEL	0.013	strongly benign-leaning
SaProt	LLR -6.38	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.77	GERP -1.4
Regional constraint	o/e 0.83	unconstrained · MANE · 18 kb · p 0.003 · regional, not allelic
Overall
CADD	11.49	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.00275% African / African-American · 2/72,810 alleles

Filtering AF 0.00071% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000556%

Overall 0.00117% 18/1,540,574 alleles · very rare exomes 16/1,388,340 · genomes 2/152,234 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00275%	36,405
Admixed American	0.00199%	50,184
European (non-Finnish)	0.00122%	81,703
South Asian	0.0012%	83,364

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.Pro59Ser
Coding: c.175C>T
MANE Select: NM_138459
dbSNP: rs764639190
Type: single nucleotide variant
Location: chr6:117675845 (GRCh38)
Gene constraint: LOEUF 0.182 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 82.01 · 9 PDB

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 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
NUS1 p.Arg217Ile 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-pro59ser (accessed [today's date]).

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