Is NUS1 p.Phe253Ser (c.758T>C) pathogenic?

NUS1 p.Phe253Ser (c.758T>C) is classified Uncertain significance in NUS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-10). AlphaMissense: likely pathogenic (0.9904); Absent from gnomAD v4.1; Associated with congenital disorder of glycosylation, type Iaa.

What condition is associated with NUS1 p.Phe253Ser (c.758T>C)?

NUS1 p.Phe253Ser (c.758T>C) is associated with congenital disorder of glycosylation, type Iaa (ClinVar).

How common is NUS1 p.Phe253Ser (c.758T>C) in the general population?

NUS1 p.Phe253Ser (c.758T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NUS1 p.Phe253Ser (c.758T>C)?

AlphaMissense predicts likely pathogenic (score 0.9904) — an in-silico prediction, not a clinical call.

NUS1 p.Phe253Ser

c.758T>C · rs2482032210 · VCV1715542

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9904 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital disorder of glycosylation, type Iaa

Computational evidence

Protein change
AlphaMissense	0.9904	likely pathogenic · top 1% in NUS1
REVEL	0.764	pathogenic-leaning
SaProt	LLR -13.20	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP -1.1, phastCons 1
Regional constraint	o/e 0.31	constrained · MANE · 9,536 bp · p 4.4e-06 · regional, not allelic
Overall
CADD	23.9	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: NUS1
Protein: p.Phe253Ser
Coding: c.758T>C
MANE Select: NM_138459
dbSNP: rs2482032210
Type: single nucleotide variant
Location: chr6:117703671 (GRCh38)
Gene constraint: LOEUF 0.182 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 82.01 · 9 PDB
Residue 253: 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 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-phe253ser (accessed [today's date]).

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