Is NTSR2 p.Arg288Trp (c.862C>T) pathogenic?

NTSR2 p.Arg288Trp (c.862C>T) is classified Uncertain significance in NTSR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: likely benign (0.1349); Ultra-rare (popmax 0.0202%, amr).

How common is NTSR2 p.Arg288Trp (c.862C>T) in the general population?

NTSR2 p.Arg288Trp (c.862C>T) is ultra-rare (popmax 0.0202%, amr) (gnomAD).

What do computational predictors say about NTSR2 p.Arg288Trp (c.862C>T)?

AlphaMissense predicts likely benign (score 0.1349) — an in-silico prediction, not a clinical call.

NTSR2 p.Arg288Trp

c.862C>T · VCV4123475

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1349 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0202%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1349	likely benign
REVEL	0.311	indeterminate
SaProt	LLR -9.41	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.4	GERP -0.87, phastCons 0.97
Regional constraint	o/e 1.00	unconstrained · MANE · 12 kb · p 0.99 · regional, not allelic
Overall
CADD	20.7	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 0.0202% Admixed American · 12/59,514 alleles

Filtering AF 0.0116% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00905%

Overall 0.0018% 29/1,610,324 alleles · ultra-rare exomes 27/1,458,018 · genomes 2/152,306 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0202%	4,960
Finnishnot grpmax-eligible	0.00157%	63,708
African / African-American	0.00133%	74,914
European (non-Finnish)	0.00119%	84,159
South Asian	0.0011%	90,540

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: NTSR2
Protein: p.Arg288Trp
Coding: c.862C>T
MANE Select: NM_012344
Type: single nucleotide variant
Location: chr2:11662003 (GRCh38)
Gene constraint: LOEUF 1.731 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25

Full NTSR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NTSR2 p.Arg288Gln Likely benign ★ same residue
NTSR2 p.Arg282Lys Benign ★★ same type
NTSR2 p.Ala190Thr Uncertain significance ★ ⚠ same type
NTSR2 p.Ala327Val Uncertain significance ★ ⚠ same type
NTSR2 p.Ala360Thr Uncertain significance ★ ⚠ same type
NTSR2 p.Ala47Val Uncertain significance ★ ⚠ same type
NTSR2 p.Ala62Thr Uncertain significance ★ ⚠ same type
NTSR2 p.Ala65Thr 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/ntsr2-p-arg288trp (accessed [today's date]).

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