Is AUP1 p.Phe23Val (c.67T>G) pathogenic?

AUP1 p.Phe23Val (c.67T>G) is classified Uncertain significance in AUP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-24). AlphaMissense: likely benign (0.085); Ultra-rare (popmax 0.0299%, afr).

How common is AUP1 p.Phe23Val (c.67T>G) in the general population?

AUP1 p.Phe23Val (c.67T>G) is ultra-rare (popmax 0.0299%, afr) (gnomAD).

What do computational predictors say about AUP1 p.Phe23Val (c.67T>G)?

AlphaMissense predicts likely benign (score 0.085) — an in-silico prediction, not a clinical call.

AUP1 p.Phe23Val

c.67T>G · rs372473706 · VCV2522573

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.085 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0299%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.085	likely benign
REVEL	0.249	benign-leaning
SaProt	LLR -6.92	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 7.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 2,826 bp · p 0.27 · regional, not allelic
Overall
CADD	20.8	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 0.0299% African / African-American · 22/73,594 alleles

Filtering AF 0.0202% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.017%

Overall 0.00154% 24/1,555,900 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0299%	3,345
Admixed American	0.00194%	51,504
Remaining individualsnot grpmax-eligible	0.00166%	60,276

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.Phe23Val
Coding: c.67T>G
MANE Select: NM_181575
dbSNP: rs372473706
Type: single nucleotide variant
Location: chr2:74529483 (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-phe23val (accessed [today's date]).

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