Is NTSR2 p.Pro218Ser (c.652C>T) pathogenic?

NTSR2 p.Pro218Ser (c.652C>T) is classified Uncertain significance in NTSR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-11). AlphaMissense: likely pathogenic (0.6713); Very rare (popmax 0.00464%, nfe).

How common is NTSR2 p.Pro218Ser (c.652C>T) in the general population?

NTSR2 p.Pro218Ser (c.652C>T) is very rare (popmax 0.00464%, nfe) (gnomAD).

What do computational predictors say about NTSR2 p.Pro218Ser (c.652C>T)?

AlphaMissense predicts likely pathogenic (score 0.6713) — an in-silico prediction, not a clinical call.

NTSR2 p.Pro218Ser

c.652C>T · rs201037497 · VCV3202665

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6713 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00464%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6713	likely pathogenic · top 7% in NTSR2
REVEL	0.415	indeterminate
SaProt	LLR -11.16	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.8	GERP 1.4, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 12 kb · p 0.99 · regional, not allelic
Overall
CADD	24.9	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 0.00464% European (non-Finnish) · 53/1,141,428 alleles

Filtering AF 0.00362% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00328%

Overall 0.00377% 58/1,537,474 alleles · very rare exomes 56/1,385,292 · genomes 2/152,182 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00508%	19,698
European (non-Finnish)grpmax	0.00464%	21,536
Finnishnot grpmax-eligible	0.00165%	60,588
African / African-American	0.00138%	72,458

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: NTSR2
Protein: p.Pro218Ser
Coding: c.652C>T
MANE Select: NM_012344
dbSNP: rs201037497
Type: single nucleotide variant
Location: chr2:11662213 (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-pro218ser (accessed [today's date]).

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