Is NLN p.Arg334Gln (c.1001G>A) pathogenic?

NLN p.Arg334Gln (c.1001G>A) is classified Uncertain significance in NLN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-01). AlphaMissense: likely benign (0.1321); Ultra-rare (popmax 0.0165%, mid).

How common is NLN p.Arg334Gln (c.1001G>A) in the general population?

NLN p.Arg334Gln (c.1001G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about NLN p.Arg334Gln (c.1001G>A)?

AlphaMissense predicts likely benign (score 0.1321) — an in-silico prediction, not a clinical call.

NLN p.Arg334Gln

c.1001G>A · VCV4120442

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1321 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1321	likely benign
REVEL	0.194	benign-leaning
SaProt	LLR -7.49	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 8.6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 101 kb · p 0.42 · regional, not allelic
Overall
CADD	24.8	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 0.0165% Middle Eastern · 1/6,060 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.00112% 18/1,614,092 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
Admixed American	0.005%	20,005
East Asian	0.00223%	44,878
Finnishnot grpmax-eligible	0.00156%	64,030
European (non-Finnish)	0.00102%	98,331

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: NLN
Protein: p.Arg334Gln
Coding: c.1001G>A
MANE Select: NM_020726
Type: single nucleotide variant
Location: chr5:65788160 (GRCh38)
Gene constraint: LOEUF 0.934 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.87 · 7 PDB
Residue 334: an α-helix

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

Similar variants

NLN p.Ala120Glu Uncertain significance ★ ⚠ same type
NLN p.Ala218Val Uncertain significance ★ ⚠ same type
NLN p.Ala36Thr Uncertain significance ★ ⚠ same type
NLN p.Arg119Gln Uncertain significance ★ ⚠ same type
NLN p.Arg131Cys Uncertain significance ★ ⚠ same type
NLN p.Arg131His Uncertain significance ★ ⚠ same type
NLN p.Arg164Gln Uncertain significance ★ ⚠ same type
NLN p.Arg261Gly 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/nln-p-arg334gln (accessed [today's date]).

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