Is ASPNAT p.Pro59Arg (c.176C>G) pathogenic?

ASPNAT p.Pro59Arg (c.176C>G) is classified Uncertain significance in ASPNAT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-07). AlphaMissense: likely benign (0.1185); Very rare (popmax 0.000348%, nfe).

How common is ASPNAT p.Pro59Arg (c.176C>G) in the general population?

ASPNAT p.Pro59Arg (c.176C>G) is very rare (popmax 0.000348%, nfe) (gnomAD).

What do computational predictors say about ASPNAT p.Pro59Arg (c.176C>G)?

AlphaMissense predicts likely benign (score 0.1185) — an in-silico prediction, not a clinical call.

ASPNAT p.Pro59Arg

c.176C>G · VCV3917341

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1185 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000348%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1185	likely benign
REVEL	0.051	moderately benign-leaning
SaProt	LLR -8.21	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.62	GERP -1.6, phastCons 0.001
Regional constraint	o/e 1.01	unconstrained · MANE · 1,534 bp · p 0.84 · regional, not allelic
Overall
CADD	14.46	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 0.000348% European (non-Finnish) · 3/861,846 alleles

Filtering AF 9.3e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.6e-05%

Overall 0.000388% 4/1,031,134 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00307%	32,522
European (non-Finnish)grpmax	0.000348%	287,282

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ASPNAT
Protein: p.Pro59Arg
Coding: c.176C>G
MANE Select: NM_178557
Type: single nucleotide variant
Location: chr4:2059687 (GRCh38)
Structure: AlphaFold pLDDT 81.36
Residue 59: the 'disordered' region

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

Similar variants

ASPNAT p.Pro59Leu Uncertain significance ★ ⚠ same residue
ASPNAT p.Pro59Ser Uncertain significance ★ ⚠ same residue
ASPNAT c.541+8C>T Benign ★★ same type
ASPNAT p.Ala35= Likely benign ★★ same type
ASPNAT p.Gly263= Likely benign ★★ same type
ASPNAT p.Pro56= Likely benign ★★ same type
ASPNAT p.Ala125Thr Uncertain significance ★ ⚠ same type
ASPNAT p.Ala225Thr 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/aspnat-p-pro59arg (accessed [today's date]).

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