Is AUP1 p.Pro153Arg (c.458C>G) pathogenic?

AUP1 p.Pro153Arg (c.458C>G) is classified Uncertain significance in AUP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-26). AlphaMissense: likely benign (0.1127); Very rare (popmax 0.000339%, nfe).

How common is AUP1 p.Pro153Arg (c.458C>G) in the general population?

AUP1 p.Pro153Arg (c.458C>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about AUP1 p.Pro153Arg (c.458C>G)?

AlphaMissense predicts likely benign (score 0.1127) — an in-silico prediction, not a clinical call.

AUP1 p.Pro153Arg

c.458C>G · rs1675335073 · VCV3132338

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1127 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1127	likely benign
REVEL	0.402	indeterminate
SaProt	LLR -9.00	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 2,826 bp · p 0.27 · regional, not allelic
Overall
CADD	29.2	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 0.000339% European (non-Finnish) · 4/1,180,010 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,614,084 alleles · very rare exomes 4/1,461,808 · genomes 0/152,276 · 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: AUP1
Protein: p.Pro153Arg
Coding: c.458C>G
MANE Select: NM_181575
dbSNP: rs1675335073
Type: single nucleotide variant
Location: chr2:74528817 (GRCh38)
Gene constraint: LOEUF 0.758 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.19 · 2 PDB

Full AUP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

HTRA2 c.-547G>C Likely benign ★★ same type
HTRA2 c.-586G>C Benign ★★ same type
AUP1 p.Ala241Val Uncertain significance ★ ⚠ same type
AUP1 p.Ala55Ser Uncertain significance ★ ⚠ same type
AUP1 p.Ala71Val Uncertain significance ★ ⚠ same type
AUP1 p.Arg144Gly Uncertain significance ★ ⚠ same type
AUP1 p.Arg144Ile Uncertain significance ★ ⚠ same type
AUP1 p.Arg173His 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/aup1-p-pro153arg (accessed [today's date]).

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