Is NTSR2 p.Arg409Gln (c.1226G>A) pathogenic?

NTSR2 p.Arg409Gln (c.1226G>A) is classified Uncertain significance in NTSR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-09). AlphaMissense: likely benign (0.0739); Ultra-rare (popmax 0.0325%, sas).

How common is NTSR2 p.Arg409Gln (c.1226G>A) in the general population?

NTSR2 p.Arg409Gln (c.1226G>A) is ultra-rare (popmax 0.0325%, sas) (gnomAD).

What do computational predictors say about NTSR2 p.Arg409Gln (c.1226G>A)?

AlphaMissense predicts likely benign (score 0.0739) — an in-silico prediction, not a clinical call.

NTSR2 p.Arg409Gln

c.1226G>A · VCV3408318

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0739 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0325%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0739	likely benign
REVEL	0.142	moderately benign-leaning
SaProt	LLR -6.46	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.2	GERP -1.9
Regional constraint	o/e 1.00	unconstrained · MANE · 12 kb · p 0.99 · regional, not allelic
Overall
CADD	0.42	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 0.0325% South Asian · 29/89,322 alleles

Filtering AF 0.0232% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.02%

Overall 0.00606% 97/1,600,368 alleles · ultra-rare exomes 81/1,448,052 · genomes 16/152,316 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0325%	3,080
East Asian	0.0269%	3,724
Admixed American	0.0207%	4,834
Middle Eastern	0.0167%	5,972
European (non-Finnish)	0.00341%	29,320
Remaining individualsnot grpmax-eligible	0.00324%	30,910
African / African-American	0.00134%	74,386

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.Arg409Gln
Coding: c.1226G>A
MANE Select: NM_012344
Type: single nucleotide variant
Location: chr2:11658486 (GRCh38)
Gene constraint: LOEUF 1.731 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.25
Residue 409: the 'disordered' region

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

Similar variants

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
NTSR2 p.Arg153Trp 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-arg409gln (accessed [today's date]).

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