Is NAPRT p.Pro137Ala (c.409C>G) pathogenic?

NAPRT p.Pro137Ala (c.409C>G) is classified Uncertain significance in NAPRT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-26). AlphaMissense: likely benign (0.0954); Very rare (popmax 6.49e-05%).

How common is NAPRT p.Pro137Ala (c.409C>G) in the general population?

NAPRT p.Pro137Ala (c.409C>G) is very rare (popmax 6.49e-05%) (gnomAD).

What do computational predictors say about NAPRT p.Pro137Ala (c.409C>G)?

AlphaMissense predicts likely benign (score 0.0954) — an in-silico prediction, not a clinical call.

NAPRT p.Pro137Ala

c.409C>G · VCV4555847

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0954 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.49e-05%)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0954	likely benign
REVEL	0.148	moderately benign-leaning
SaProt	LLR -5.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.5	GERP 1.5, phastCons 1
Regional constraint	o/e 1.12	unconstrained · MANE · 3,477 bp · p 0.0014 · regional, not allelic
Overall
CADD	22.8	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 6.49e-05%

Overall 6.49e-05% 1/1,541,392 alleles · very rare exomes 1/1,389,022 · genomes 0/152,370 · 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: NAPRT
Protein: p.Pro137Ala
Coding: c.409C>G
MANE Select: NM_145201
Type: single nucleotide variant
Location: chr8:143577685 (GRCh38)
Gene constraint: LOEUF 1.486 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.94 · 1 PDB
Residue 137: an α-helix

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

Similar variants

NAPRT c.1447-7C>G Benign ★★ same type
NAPRT p.Asp320= Benign ★★ same type
NAPRT p.Pro117= Benign/Likely benign ★★ same type
NAPRT p.Ala13Gly Uncertain significance ★ ⚠ same type
NAPRT p.Ala159Thr Uncertain significance ★ ⚠ same type
NAPRT p.Ala231Val Uncertain significance ★ ⚠ same type
NAPRT p.Ala234Pro Uncertain significance ★ ⚠ same type
NAPRT p.Ala23Thr 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/naprt-p-pro137ala (accessed [today's date]).

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