Is NLN p.Cys199Arg (c.595T>C) pathogenic?

NLN p.Cys199Arg (c.595T>C) is classified Uncertain significance in NLN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-21). AlphaMissense: ambiguous (0.5559); Very rare (popmax 0.00272%, nfe).

How common is NLN p.Cys199Arg (c.595T>C) in the general population?

NLN p.Cys199Arg (c.595T>C) is very rare (popmax 0.00272%, nfe) (gnomAD).

What do computational predictors say about NLN p.Cys199Arg (c.595T>C)?

AlphaMissense predicts ambiguous (score 0.5559) — an in-silico prediction, not a clinical call.

NLN p.Cys199Arg

c.595T>C · VCV4557965

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5559 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00272%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5559	ambiguous
REVEL	0.277	benign-leaning
SaProt	LLR -12.04	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 101 kb · p 0.42 · regional, not allelic
Overall
CADD	26.1	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 0.00272% European (non-Finnish) · 28/1,028,836 alleles

Filtering AF 0.00189% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00162%

Overall 0.00201% 29/1,439,216 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00272%	36,744
East Asian	0.00232%	43,106

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.Cys199Arg
Coding: c.595T>C
MANE Select: NM_020726
Type: single nucleotide variant
Location: chr5:65780215 (GRCh38)
Gene constraint: LOEUF 0.934 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.87 · 7 PDB
Residue 199: 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-cys199arg (accessed [today's date]).

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