Is IPO4 p.Pro494Thr (c.1480C>A) pathogenic?

IPO4 p.Pro494Thr (c.1480C>A) is classified Benign in IPO4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-02-09). AlphaMissense: likely benign (0.0724); Low-frequency (popmax 2.37%, afr).

How common is IPO4 p.Pro494Thr (c.1480C>A) in the general population?

IPO4 p.Pro494Thr (c.1480C>A) is low-frequency (popmax 2.37%, afr) (gnomAD).

What do computational predictors say about IPO4 p.Pro494Thr (c.1480C>A)?

AlphaMissense predicts likely benign (score 0.0724) — an in-silico prediction, not a clinical call.

IPO4 p.Pro494Thr

c.1480C>A · rs145779241 · VCV776825

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0724 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.37%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0724	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -8.90	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 3.2	GERP -2.9, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 4,391 bp · p 0.73 · regional, not allelic
Overall
CADD	15.54	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.37% African / African-American · 1,780/75,042 alleles

Filtering AF 2.28% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.24%

Overall 0.125% 2,015/1,614,098 alleles · low-frequency exomes 996/1,461,810 · genomes 1,019/152,288 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.37%	42
Remaining individualsnot grpmax-eligible	0.173%	579
Admixed American	0.135%	741
Middle Eastern	0.0825%	1,212
South Asian	0.0176%	5,693
European (non-Finnish)	0.00212%	47,201

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: IPO4
Protein: p.Pro494Thr
Coding: c.1480C>A
MANE Select: NM_024658
dbSNP: rs145779241
Type: single nucleotide variant
Location: chr14:24184909 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.05 · 4 PDB

Full IPO4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IPO4 p.Arg20Cys Benign ★★ ⚠ same type
IMP4 p.Ala21Val Uncertain significance ★ ⚠ same type
IMP4 p.Ala282Thr Uncertain significance ★ ⚠ same type
IMP4 p.Arg126Gln Uncertain significance ★ ⚠ same type
IMP4 p.Arg170Trp Uncertain significance ★ ⚠ same type
IMP4 p.Arg194Cys Uncertain significance ★ ⚠ same type
IMP4 p.Arg198Gln Uncertain significance ★ ⚠ same type
IMP4 p.Arg204Gln 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/ipo4-p-pro494thr (accessed [today's date]).

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