Is NLN p.Arg262Ile (c.785G>T) pathogenic?

NLN p.Arg262Ile (c.785G>T) is classified Uncertain significance in NLN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-24). AlphaMissense: ambiguous (0.3627); Very rare (popmax 8.5e-05%, nfe).

How common is NLN p.Arg262Ile (c.785G>T) in the general population?

NLN p.Arg262Ile (c.785G>T) is very rare (popmax 8.5e-05%, nfe) (gnomAD).

What do computational predictors say about NLN p.Arg262Ile (c.785G>T)?

AlphaMissense predicts ambiguous (score 0.3627) — an in-silico prediction, not a clinical call.

NLN p.Arg262Ile

c.785G>T · rs2546275075 · VCV3200450

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3627 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.5e-05%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3627	ambiguous
REVEL	0.356	indeterminate
SaProt	LLR -11.27	damaging
Splicing
SpliceAI	Δ0.29	donor loss · deltas
Pangolin	Δ0.24	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 101 kb · p 0.42 · regional, not allelic
Overall
CADD	25.5	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 8.5e-05% European (non-Finnish) · 1/1,176,588 alleles

Overall 6.86e-05% 1/1,457,774 alleles · very rare

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.Arg262Ile
Coding: c.785G>T
MANE Select: NM_020726
dbSNP: rs2546275075
Type: single nucleotide variant
Location: chr5:65781384 (GRCh38)
Gene constraint: LOEUF 0.934 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.87 · 7 PDB
Residue 262: 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-arg262ile (accessed [today's date]).

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