Is NCSTN p.Asp381His (c.1141G>C) pathogenic?

NCSTN p.Asp381His (c.1141G>C) is classified Uncertain significance in NCSTN (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-02). AlphaMissense: likely pathogenic (0.9481); Very rare (popmax 0.0011%, sas).

How common is NCSTN p.Asp381His (c.1141G>C) in the general population?

NCSTN p.Asp381His (c.1141G>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about NCSTN p.Asp381His (c.1141G>C)?

AlphaMissense predicts likely pathogenic (score 0.9481) — an in-silico prediction, not a clinical call.

NCSTN p.Asp381His

c.1141G>C · VCV4811605

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9481 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9481	likely pathogenic
REVEL	0.785	moderately pathogenic-leaning
SaProt	LLR -15.21	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 2,519 bp · p 0.73 · regional, not allelic
Overall
CADD	29.1	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

Grpmax group 0.0011% South Asian · 1/91,082 alleles

Overall 6.2e-05% 1/1,614,154 alleles · very rare exomes 1/1,461,892 · genomes 0/152,262 · 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: NCSTN
Protein: p.Asp381His
Coding: c.1141G>C
MANE Select: NM_015331
Type: single nucleotide variant
Location: chr1:160353199 (GRCh38)
Gene constraint: LOEUF 0.343 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 89.73 · 30 PDB

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-asp381his (accessed [today's date]).

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