Is NANS p.Val35Ala (c.104T>C) pathogenic?

NANS p.Val35Ala (c.104T>C) is classified Uncertain significance in NANS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-01). AlphaMissense: likely benign (0.2269); Ultra-rare (popmax 0.027%, eas).

How common is NANS p.Val35Ala (c.104T>C) in the general population?

NANS p.Val35Ala (c.104T>C) is ultra-rare (popmax 0.027%, eas) (gnomAD).

What do computational predictors say about NANS p.Val35Ala (c.104T>C)?

AlphaMissense predicts likely benign (score 0.2269) — an in-silico prediction, not a clinical call.

NANS p.Val35Ala

c.104T>C · rs540341211 · VCV1511077

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2269 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.027%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

⚠ 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	0.2269	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -9.39	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 6	GERP 2, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 26 kb · p 0.0018 · regional, not allelic
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.027% East Asian · 12/44,448 alleles

Filtering AF 0.0155% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0122%

Overall 0.000746% 12/1,609,182 alleles · ultra-rare exomes 11/1,456,898 · genomes 1/152,284 · joint denominator

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.Val35Ala
Coding: c.104T>C
MANE Select: NM_018946
dbSNP: rs540341211
Type: single nucleotide variant
Location: chr9:98056912 (GRCh38)

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

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-val35ala (accessed [today's date]).

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