Is NLN p.Arg577His (c.1730G>A) pathogenic?

NLN p.Arg577His (c.1730G>A) is classified Uncertain significance in NLN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-03). AlphaMissense: likely benign (0.3103); Rare (popmax 0.12%, eas).

How common is NLN p.Arg577His (c.1730G>A) in the general population?

NLN p.Arg577His (c.1730G>A) is rare (popmax 0.12%, eas) (gnomAD).

What do computational predictors say about NLN p.Arg577His (c.1730G>A)?

AlphaMissense predicts likely benign (score 0.3103) — an in-silico prediction, not a clinical call.

NLN p.Arg577His

c.1730G>A · VCV3406003

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3103 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.12%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3103	likely benign
REVEL	0.41	indeterminate
SaProt	LLR -13.45	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 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 101 kb · p 0.42 · regional, not allelic
Overall
CADD	33.0	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 0.12% East Asian · 54/44,874 alleles

Filtering AF 0.0946% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0855%

Overall 0.00465% 75/1,613,920 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.12%	831
Admixed American	0.0183%	5,456
Remaining individualsnot grpmax-eligible	0.0048%	20,836
South Asian	0.0011%	91,076
European (non-Finnish)	0.000508%	196,662

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.Arg577His
Coding: c.1730G>A
MANE Select: NM_020726
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.Arg577Pro 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-arg577his (accessed [today's date]).

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