Is NANS p.Pro18Leu (c.53C>T) pathogenic?

NANS p.Pro18Leu (c.53C>T) is classified Likely benign in NANS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-06). AlphaMissense: ambiguous (0.5267); Rare (popmax 0.204%, nfe).

How common is NANS p.Pro18Leu (c.53C>T) in the general population?

NANS p.Pro18Leu (c.53C>T) is rare (popmax 0.204%, nfe) (gnomAD).

What do computational predictors say about NANS p.Pro18Leu (c.53C>T)?

AlphaMissense predicts ambiguous (score 0.5267) — an in-silico prediction, not a clinical call.

NANS p.Pro18Leu

c.53C>T · rs139706489 · VCV728546

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5267 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.204%, nfe)

Computational evidence

Protein change
AlphaMissense	0.5267	ambiguous
REVEL	0.378	indeterminate
SaProt	LLR -12.71	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 2, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 26 kb · p 0.0018 · regional, not allelic
Overall
CADD	32.0	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 0.204% European (non-Finnish) · 2,407/1,179,430 alleles

Filtering AF 0.197% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.194%

Overall 0.18% 2,908/1,612,304 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.554%	181
European (non-Finnish)grpmax	0.204%	490
Remaining individualsnot grpmax-eligible	0.181%	552
Admixed American	0.0333%	2,999
African / African-American	0.0187%	5,348
Ashkenazi Jewishnot grpmax-eligible	0.00677%	14,762
South Asian	0.0011%	90,992

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: NANS
Protein: p.Pro18Leu
Coding: c.53C>T
MANE Select: NM_018946
dbSNP: rs139706489
Type: single nucleotide variant
Location: chr9:98056861 (GRCh38)
Gene constraint: LOEUF 1.053 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.04 · 1 PDB

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

Similar variants

NANS p.Pro18Ala Uncertain significance ★★ ⚠ same residue
NANS c.448+1G>A Pathogenic/Likely pathogenic ★★ same type
NANS p.Glu258Ter Pathogenic/Likely pathogenic ★★ same type
NANS p.Ala102Thr Uncertain significance ★★ ⚠ same type
NANS p.Arg264Gln Uncertain significance ★★ ⚠ same type
NANS p.Arg267His Uncertain significance ★★ same type
NANS p.Gln94Glu Uncertain significance ★★ ⚠ same type
NANS p.Ile301Met 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/nans-p-pro18leu (accessed [today's date]).

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