Is PRUNE1 p.Val433Ile (c.1297G>A) pathogenic?

PRUNE1 p.Val433Ile (c.1297G>A) is classified Uncertain significance in PRUNE1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-27). AlphaMissense: likely benign (0.0575); Very rare (popmax 0.00432%, nfe).

How common is PRUNE1 p.Val433Ile (c.1297G>A) in the general population?

PRUNE1 p.Val433Ile (c.1297G>A) is very rare (popmax 0.00432%, nfe) (gnomAD).

What do computational predictors say about PRUNE1 p.Val433Ile (c.1297G>A)?

AlphaMissense predicts likely benign (score 0.0575) — an in-silico prediction, not a clinical call.

PRUNE1 p.Val433Ile

c.1297G>A · rs373152187 · VCV2050948

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0575 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00432%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0575	likely benign
REVEL	0.068	moderately benign-leaning
SaProt	LLR -5.30	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 0.3	GERP -2.4, phastCons 0.001
Regional constraint	o/e 0.82	unconstrained · MANE · 26 kb · p 3.4e-05 · regional, not allelic
Overall
CADD	1.127	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 0.00432% European (non-Finnish) · 51/1,180,040 alleles

Filtering AF 0.00334% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00302%

Overall 0.00353% 57/1,614,014 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00432%	23,138
African / African-American	0.00267%	37,460
South Asian	0.0022%	45,540
Admixed American	0.00167%	59,996
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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: PRUNE1
Protein: p.Val433Ile
Coding: c.1297G>A
MANE Select: NM_021222
dbSNP: rs373152187
Type: single nucleotide variant
Location: chr1:151034169 (GRCh38)
Gene constraint: LOEUF 0.902 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.61
Residue 433: a UniProt-annotated variant site (in nmihba)

Full PRUNE1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PRUNE1 c.132+2T>C Pathogenic ★★ same type
PRUNE1 c.521-2A>G Pathogenic/Likely pathogenic ★★ same type
PRUNE1 p.Arg128Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
PRUNE1 p.Arg66Ter Pathogenic/Likely pathogenic ★★ same type
PRUNE1 p.Asp106Asn Pathogenic/Likely pathogenic ★★ same type
PRUNE1 p.Asp30Asn Pathogenic/Likely pathogenic ★★ same type
PRUNE1 p.Ala39Pro Uncertain significance ★★ ⚠ same type
PRUNE1 p.Asp87Asn 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/prune1-p-val433ile (accessed [today's date]).

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