Is NLGN3 p.Pro77Ser (c.229C>T) pathogenic?

NLGN3 p.Pro77Ser (c.229C>T) is classified Uncertain significance in NLGN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-26). AlphaMissense: likely benign (0.138); Very rare (popmax 0.000448%, nfe); Associated with Inborn genetic diseases.

What condition is associated with NLGN3 p.Pro77Ser (c.229C>T)?

NLGN3 p.Pro77Ser (c.229C>T) is associated with Inborn genetic diseases (ClinVar).

How common is NLGN3 p.Pro77Ser (c.229C>T) in the general population?

NLGN3 p.Pro77Ser (c.229C>T) is very rare (popmax 0.000448%, nfe) (gnomAD).

What do computational predictors say about NLGN3 p.Pro77Ser (c.229C>T)?

AlphaMissense predicts likely benign (score 0.138) — an in-silico prediction, not a clinical call.

NLGN3 p.Pro77Ser

c.229C>T · rs1211820354 · VCV1789226

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.138 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000448%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.138	likely benign
REVEL	0.563	indeterminate
SaProt	LLR -10.34	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.1, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 7,479 bp · p 1e-06 · regional, not allelic
Overall
CADD	23.2	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 0.000448% European (non-Finnish) · 4/892,518 alleles

Filtering AF 0.000105% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.1e-05%

Overall 0.000332% 4/1,206,055 alleles · very rare exomes 2/1,094,903 · genomes 2/111,152 · joint denominator

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: NLGN3
Protein: p.Pro77Ser
Coding: c.229C>T
MANE Select: NM_181303
dbSNP: rs1211820354
Type: single nucleotide variant
Location: chrX:71147978 (GRCh38)
Structure: AlphaFold pLDDT 76.80 · 1 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NLGN3 p.Arg785Cys Uncertain significance ★★ ⚠ same condition
NLGN3 p.Leu31Phe Uncertain significance ★★ ⚠ same condition
NLGN3 p.Leu477Phe Uncertain significance ★★ ⚠ same condition
NLGN3 p.Thr783Met Uncertain significance ★★ ⚠ same condition
NLGN3 p.Val346Met Uncertain significance ★★ ⚠ same condition
NLGN3 p.Ala750= Benign ★★ same condition
NLGN3 p.Asn138= Likely benign ★★ same condition
NLGN3 p.Asn138Ser Likely benign ★★ same condition

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-pro77ser (accessed [today's date]).

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