Is NAPRT p.Ala243Val (c.728C>T) pathogenic?

NAPRT p.Ala243Val (c.728C>T) is classified Uncertain significance in NAPRT (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-17). AlphaMissense: likely benign (0.0788); Ultra-rare (popmax 0.022%, mid).

How common is NAPRT p.Ala243Val (c.728C>T) in the general population?

NAPRT p.Ala243Val (c.728C>T) is ultra-rare (popmax 0.022%, mid) (gnomAD).

What do computational predictors say about NAPRT p.Ala243Val (c.728C>T)?

AlphaMissense predicts likely benign (score 0.0788) — an in-silico prediction, not a clinical call.

NAPRT p.Ala243Val

c.728C>T · rs199843319 · VCV2347082

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0788 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.022%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0788	likely benign
REVEL	0.085	moderately benign-leaning
SaProt	LLR -7.83	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.29 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1	GERP -1.3
Regional constraint	o/e 1.12	unconstrained · MANE · 3,477 bp · p 0.0014 · regional, not allelic
Overall
CADD	8.74	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 0.022% Middle Eastern · 1/4,536 alleles

Filtering AF 0.00937% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00881%

Overall 0.0115% 185/1,607,218 alleles · ultra-rare exomes 170/1,454,896 · genomes 15/152,322 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.125%	797
Middle Easterngrpmax	0.022%	4,536
European (non-Finnish)	0.011%	9,131
African / African-American	0.0107%	9,366
Remaining individualsnot grpmax-eligible	0.00966%	10,350
South Asian	0.00441%	22,655

Ashkenazi Jewish 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: NAPRT
Protein: p.Ala243Val
Coding: c.728C>T
MANE Select: NM_145201
dbSNP: rs199843319
Type: single nucleotide variant
Location: chr8:143576799 (GRCh38)
Gene constraint: LOEUF 1.486 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.94 · 1 PDB
Residue 243: 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-ala243val (accessed [today's date]).

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