Is NANS p.Met1Val (c.1A>G) pathogenic?

NANS p.Met1Val (c.1A>G) is classified Likely pathogenic in NANS (ClinVar, Single submitter, 2 submitters; last evaluated 2019-05-01). Ultra-rare (popmax 0.0169%, mid); Associated with spondyloepimetaphyseal dysplasia, Genevieve type.

What condition is associated with NANS p.Met1Val (c.1A>G)?

NANS p.Met1Val (c.1A>G) is associated with spondyloepimetaphyseal dysplasia, Genevieve type (ClinVar).

How common is NANS p.Met1Val (c.1A>G) in the general population?

NANS p.Met1Val (c.1A>G) is ultra-rare (popmax 0.0169%, mid) (gnomAD).

NANS p.Met1Val

Q: How is Spondyloepimetaphyseal dysplasia, Geneviève type inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.1A>G · rs369033671 · VCV810396

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0169%, mid)

Conditions

spondyloepimetaphyseal dysplasia, Genevieve type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function
REVEL	0.422	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Overall
CADD	23.1	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0169% Middle Eastern · 1/5,928 alleles

Filtering AF 0.00287% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00196%

Overall 0.00144% 23/1,592,314 alleles · ultra-rare exomes 22/1,440,680 · genomes 1/151,634 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0169%	5,928
South Asian	0.00662%	15,116
Remaining individualsnot grpmax-eligible	0.00493%	20,277
East Asian	0.00459%	21,780
European (non-Finnish)	0.000942%	106,122

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.Met1Val
Coding: c.1A>G
MANE Select: NM_018946
dbSNP: rs369033671
Type: single nucleotide variant
Location: chr9:98056809 (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

Disease context

spondyloepimetaphyseal dysplasia, Genevieve type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Spondyloepimetaphyseal dysplasia, Geneviève type (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

NANS c.448+1G>A Pathogenic/Likely pathogenic ★★ same condition
NANS p.Glu258Ter Pathogenic/Likely pathogenic ★★ same condition
NANS p.Pro18Ala Uncertain significance ★★ ⚠ same condition
NANS p.Ala51= Benign ★★ same condition
NANS p.Asp34= Benign ★★ same condition
NANS p.Trp245Ter Likely pathogenic ★ same condition
NANS p.Arg237Cys Conflicting classifications of pathogenicity ★ ⚠ same condition
NANS p.Ile223Thr Uncertain significance ★ ⚠ same condition

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-met1val (accessed [today's date]).

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