Is NCSTN p.Pro593Ser (c.1777C>T) pathogenic?

NCSTN p.Pro593Ser (c.1777C>T) is classified Uncertain significance in NCSTN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-19). AlphaMissense: likely benign (0.0736); Absent from gnomAD v4.1.

How common is NCSTN p.Pro593Ser (c.1777C>T) in the general population?

NCSTN p.Pro593Ser (c.1777C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NCSTN p.Pro593Ser (c.1777C>T)?

AlphaMissense predicts likely benign (score 0.0736) — an in-silico prediction, not a clinical call.

NCSTN p.Pro593Ser

c.1777C>T · rs1235558184 · VCV2127967

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0736 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0736	likely benign
REVEL	0.171	moderately benign-leaning
SaProt	LLR -7.59	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP 2, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 2,578 bp · p 5.9e-08 · regional, not allelic
Overall
CADD	20.6	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

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: NCSTN
Protein: p.Pro593Ser
Coding: c.1777C>T
MANE Select: NM_015331
dbSNP: rs1235558184
Type: single nucleotide variant
Location: chr1:160356737 (GRCh38)
Gene constraint: LOEUF 0.343 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 89.73 · 30 PDB
Residue 593: a β-strand

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

Similar variants

NCSTN p.Ala207Pro Uncertain significance ★★ ⚠ same type
NCSTN p.Ala298Thr Uncertain significance ★★ ⚠ same type
NCSTN p.Ala484Thr Uncertain significance ★★ same type
NCSTN p.Ala48Ser Uncertain significance ★★ ⚠ same type
NCSTN p.Ala497Val Uncertain significance ★★ ⚠ same type
NCSTN p.Ala664Gly Uncertain significance ★★ same type
NCSTN p.Ala664Thr Uncertain significance ★★ same type
NCSTN p.Arg105Trp Uncertain significance ★★ ⚠ same type

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/ncstn-p-pro593ser (accessed [today's date]).

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