Is NANS p.Pro324Ser (c.970C>T) pathogenic?

NANS p.Pro324Ser (c.970C>T) is classified Uncertain significance in NANS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-15). AlphaMissense: ambiguous (0.5477); Very rare (popmax 0.00267%, afr); Associated with Inborn genetic diseases.

What condition is associated with NANS p.Pro324Ser (c.970C>T)?

NANS p.Pro324Ser (c.970C>T) is associated with Inborn genetic diseases (ClinVar).

How common is NANS p.Pro324Ser (c.970C>T) in the general population?

NANS p.Pro324Ser (c.970C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about NANS p.Pro324Ser (c.970C>T)?

AlphaMissense predicts ambiguous (score 0.5477) — an in-silico prediction, not a clinical call.

NANS p.Pro324Ser

c.970C>T · rs763824205 · VCV3174793

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5477 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5477	ambiguous
REVEL	0.233	benign-leaning
SaProt	LLR -9.26	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 26 kb · p 0.0018 · regional, not allelic
Overall
CADD	24.3	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 0.00267% African / African-American · 2/74,888 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000186% 3/1,613,980 alleles · very rare exomes 2/1,461,884 · genomes 1/152,096 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,444
European (non-Finnish)	8.47e-05%	1,180,020

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.Pro324Ser
Coding: c.970C>T
MANE Select: NM_018946
dbSNP: rs763824205
Type: single nucleotide variant
Location: chr9:98082945 (GRCh38)
Gene constraint: LOEUF 1.053 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.04 · 1 PDB
Residue 324: the afp-like domain; a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NANS p.Ala102Thr Uncertain significance ★★ ⚠ same condition
NANS p.Arg264Gln Uncertain significance ★★ ⚠ same condition
NANS p.Arg267His Uncertain significance ★★ same condition
NANS p.Gln94Glu Uncertain significance ★★ ⚠ same condition
NANS p.Ile301Met Uncertain significance ★★ ⚠ same condition
NANS p.Lys358Arg Uncertain significance ★★ ⚠ same condition
NANS p.Lys61Arg Uncertain significance ★★ ⚠ same condition
NANS p.Ser201Leu 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-pro324ser (accessed [today's date]).

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