Is NLN p.Arg577Pro (c.1730G>C) pathogenic?

NLN p.Arg577Pro (c.1730G>C) is classified Uncertain significance in NLN (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-20). AlphaMissense: likely pathogenic (0.99); Very rare (popmax 0.0028%, nfe).

How common is NLN p.Arg577Pro (c.1730G>C) in the general population?

NLN p.Arg577Pro (c.1730G>C) is very rare (popmax 0.0028%, nfe) (gnomAD).

What do computational predictors say about NLN p.Arg577Pro (c.1730G>C)?

AlphaMissense predicts likely pathogenic (score 0.99) — an in-silico prediction, not a clinical call.

NLN p.Arg577Pro

c.1730G>C · rs181089957 · VCV3200448

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.99 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0028%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.99	likely pathogenic · top 2% in NLN
REVEL	0.66	pathogenic-leaning
SaProt	LLR -16.80	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 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 101 kb · p 0.42 · regional, not allelic
Overall
CADD	34.0	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

Grpmax group 0.0028% European (non-Finnish) · 33/1,179,980 alleles

Filtering AF 0.002% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00175%

Overall 0.00204% 33/1,613,802 alleles · very rare exomes 32/1,461,678 · genomes 1/152,124 · 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: NLN
Protein: p.Arg577Pro
Coding: c.1730G>C
MANE Select: NM_020726
dbSNP: rs181089957
Type: single nucleotide variant
Location: chr5:65810052 (GRCh38)
Gene constraint: LOEUF 0.934 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.87 · 7 PDB
Residue 577: an α-helix

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

Similar variants

NLN p.Arg577His Uncertain significance ★ ⚠ same residue
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

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-arg577pro (accessed [today's date]).

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