Is NTSR2 p.Leu45Pro (c.134T>C) pathogenic?

NTSR2 p.Leu45Pro (c.134T>C) is classified Uncertain significance in NTSR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-05). AlphaMissense: likely benign (0.2084); Ultra-rare (popmax 0.0116%, nfe).

How common is NTSR2 p.Leu45Pro (c.134T>C) in the general population?

NTSR2 p.Leu45Pro (c.134T>C) is ultra-rare (popmax 0.0116%, nfe) (gnomAD).

What do computational predictors say about NTSR2 p.Leu45Pro (c.134T>C)?

AlphaMissense predicts likely benign (score 0.2084) — an in-silico prediction, not a clinical call.

NTSR2 p.Leu45Pro

c.134T>C · rs564129329 · VCV2332446

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2084 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0116%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2084	likely benign
REVEL	0.284	benign-leaning
SaProt	LLR -11.15	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.31	GERP 1.6
Regional constraint	o/e 1.00	unconstrained · MANE · 12 kb · p 0.99 · regional, not allelic
Overall
CADD	21.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0116% European (non-Finnish) · 132/1,137,098 alleles

Filtering AF 0.00997% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00938%

Overall 0.00918% 139/1,513,480 alleles · ultra-rare exomes 128/1,361,310 · genomes 11/152,170 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0116%	8,614
Remaining individualsnot grpmax-eligible	0.0102%	9,783
Finnishnot grpmax-eligible	0.00205%	48,892

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.Leu45Pro
Coding: c.134T>C
MANE Select: NM_012344
dbSNP: rs564129329
Type: single nucleotide variant
Location: chr2:11669996 (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.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-leu45pro (accessed [today's date]).

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