Is NCSTN p.Phe682= (c.2046C>T) pathogenic?

NCSTN p.Phe682= (c.2046C>T) is classified Likely benign in NCSTN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-17). Ultra-rare (popmax 0.0117%, nfe).

How common is NCSTN p.Phe682= (c.2046C>T) in the general population?

NCSTN p.Phe682= (c.2046C>T) is ultra-rare (popmax 0.0117%, nfe) (gnomAD).

NCSTN p.Phe682=

c.2046C>T · rs202179908 · VCV1579100

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.12	GERP 1, phastCons 0.92
Overall
CADD	7.842	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0117% European (non-Finnish) · 138/1,180,042 alleles

Filtering AF 0.01% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00948%

Overall 0.00923% 149/1,614,074 alleles · ultra-rare exomes 131/1,461,890 · genomes 18/152,184 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0128%	7,811
European (non-Finnish)grpmax	0.0117%	8,551
African / African-American	0.00267%	37,455
Admixed American	0.00167%	60,008

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe682=
Coding: c.2046C>T
MANE Select: NM_015331
dbSNP: rs202179908
Type: single nucleotide variant
Location: chr1:160358187 (GRCh38)
Gene constraint: LOEUF 0.343 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 89.73 · 30 PDB
Residue 682: an α-helix

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-phe682 (accessed [today's date]).

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