Is NANS p.Pro208Ala (c.622C>G) pathogenic?

NANS p.Pro208Ala (c.622C>G) is classified Uncertain significance in NANS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-12). AlphaMissense: likely benign (0.1716); Very rare (popmax 0.00178%, amr).

How common is NANS p.Pro208Ala (c.622C>G) in the general population?

NANS p.Pro208Ala (c.622C>G) is very rare (popmax 0.00178%, amr) (gnomAD).

What do computational predictors say about NANS p.Pro208Ala (c.622C>G)?

AlphaMissense predicts likely benign (score 0.1716) — an in-silico prediction, not a clinical call.

NANS p.Pro208Ala

c.622C>G · rs1245754029 · VCV1936534

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1716 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00178%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1716	likely benign
REVEL	0.245	benign-leaning
SaProt	LLR -11.34	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	Δ0.48	acceptor loss, 16 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 5.9	GERP 2, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 26 kb · p 0.0018 · regional, not allelic
Overall
CADD	25.9	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 0.00178% Admixed American · 1/56,186 alleles

Overall 6.31e-05% 1/1,585,362 alleles · very rare exomes 1/1,433,038 · genomes 0/152,324 · 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.Pro208Ala
Coding: c.622C>G
MANE Select: NM_018946
dbSNP: rs1245754029
Type: single nucleotide variant
Location: chr9:98080834 (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 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
NANS p.Lys358Arg 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-pro208ala (accessed [today's date]).

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