Is NLGN3 p.Pro149Ser (c.445C>T) pathogenic?

NLGN3 p.Pro149Ser (c.445C>T) is classified Uncertain significance in NLGN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-05). AlphaMissense: likely pathogenic (0.9744); Absent from gnomAD v4.1.

How common is NLGN3 p.Pro149Ser (c.445C>T) in the general population?

NLGN3 p.Pro149Ser (c.445C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NLGN3 p.Pro149Ser (c.445C>T)?

AlphaMissense predicts likely pathogenic (score 0.9744) — an in-silico prediction, not a clinical call.

NLGN3 p.Pro149Ser

c.445C>T · VCV4074609

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9744 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9744	likely pathogenic
REVEL	0.895	moderately pathogenic-leaning
SaProt	LLR -13.86	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 7,479 bp · p 1e-06 · regional, not allelic
Overall
CADD	27.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NLGN3
Protein: p.Pro149Ser
Coding: c.445C>T
MANE Select: NM_181303
Type: single nucleotide variant
Location: chrX:71148194 (GRCh38)
Structure: AlphaFold pLDDT 76.80 · 1 PDB

Full NLGN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NLGN3 p.Pro149= Likely benign ★ same residue
NLGN3 p.Arg748Gln Uncertain significance ★★ ⚠ same type
NLGN3 p.Arg785Cys Uncertain significance ★★ ⚠ same type
NLGN3 p.Arg785His Uncertain significance ★★ ⚠ same type
NLGN3 p.Arg847Gln Uncertain significance ★★ ⚠ same type
NLGN3 p.Asp492Asn Uncertain significance ★★ ⚠ same type
NLGN3 p.Leu31Phe Uncertain significance ★★ ⚠ same type
NLGN3 p.Leu477Phe 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/nlgn3-p-pro149ser (accessed [today's date]).

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