Is NANS p.Arg151His (c.452G>A) pathogenic?

NANS p.Arg151His (c.452G>A) is classified Uncertain significance in NANS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2022-03-13). AlphaMissense: likely benign (0.2577); Very rare (popmax 0.0022%, sas); Associated with spondyloepimetaphyseal dysplasia, Genevieve type.

What condition is associated with NANS p.Arg151His (c.452G>A)?

NANS p.Arg151His (c.452G>A) is associated with spondyloepimetaphyseal dysplasia, Genevieve type (ClinVar).

How common is NANS p.Arg151His (c.452G>A) in the general population?

NANS p.Arg151His (c.452G>A) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about NANS p.Arg151His (c.452G>A)?

AlphaMissense predicts likely benign (score 0.2577) — an in-silico prediction, not a clinical call.

NANS p.Arg151His

Q: How is Spondyloepimetaphyseal dysplasia, Geneviève type inherited?

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

c.452G>A · rs140402727 · VCV235187

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2577 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

spondyloepimetaphyseal dysplasia, Genevieve type

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.2577	likely benign
REVEL	0.298	indeterminate
SaProt	LLR -10.74	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 26 kb · p 0.0018 · regional, not allelic
Overall
CADD	28.6	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 0.0022% South Asian · 2/91,086 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00112% 18/1,614,014 alleles · very rare exomes 17/1,461,870 · genomes 1/152,144 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,543
European (non-Finnish)	0.00136%	73,751

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.Arg151His
Coding: c.452G>A
MANE Select: NM_018946
dbSNP: rs140402727
Type: single nucleotide variant
Location: chr9:98078196 (GRCh38)

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

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-arg151his (accessed [today's date]).

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