Is NLN p.Pro54Leu (c.161C>T) pathogenic?

NLN p.Pro54Leu (c.161C>T) is classified Uncertain significance in NLN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-12). AlphaMissense: likely benign (0.2159); Ultra-rare (popmax 0.0114%, nfe).

How common is NLN p.Pro54Leu (c.161C>T) in the general population?

NLN p.Pro54Leu (c.161C>T) is ultra-rare (popmax 0.0114%, nfe) (gnomAD).

What do computational predictors say about NLN p.Pro54Leu (c.161C>T)?

AlphaMissense predicts likely benign (score 0.2159) — an in-silico prediction, not a clinical call.

NLN p.Pro54Leu

c.161C>T · rs139431004 · VCV2392376

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2159 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0114%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2159	likely benign
REVEL	0.417	indeterminate
SaProt	LLR -10.74	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 7.6	GERP 4.6, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 101 kb · p 0.42 · regional, not allelic
Overall
CADD	27.4	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 0.0114% European (non-Finnish) · 134/1,179,830 alleles

Filtering AF 0.00978% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00912%

Overall 0.00868% 140/1,613,610 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0114%	8,805
Remaining individualsnot grpmax-eligible	0.0096%	10,412

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.Pro54Leu
Coding: c.161C>T
MANE Select: NM_020726
dbSNP: rs139431004
Type: single nucleotide variant
Location: chr5:65758686 (GRCh38)
Gene constraint: LOEUF 0.934 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.87 · 7 PDB
Residue 54: 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-pro54leu (accessed [today's date]).

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