Is IPO4 p.Ala74Val (c.221C>T) pathogenic?

IPO4 p.Ala74Val (c.221C>T) is classified Uncertain significance in IPO4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-05). AlphaMissense: likely benign (0.0734); Ultra-rare (popmax 0.0165%, mid).

How common is IPO4 p.Ala74Val (c.221C>T) in the general population?

IPO4 p.Ala74Val (c.221C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about IPO4 p.Ala74Val (c.221C>T)?

AlphaMissense predicts likely benign (score 0.0734) — an in-silico prediction, not a clinical call.

IPO4 p.Ala74Val

c.221C>T · rs369567721 · VCV2270578

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0734 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0734	likely benign
REVEL	0.037	moderately benign-leaning
SaProt	LLR -7.90	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 0.1	GERP -4.7
Regional constraint	o/e 0.99	unconstrained · MANE · 4,391 bp · p 0.73 · regional, not allelic
Overall
CADD	17.19	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 0.0165% Middle Eastern · 1/6,070 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000806% 13/1,612,152 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,070
African / African-American	0.00401%	24,967
South Asian	0.0011%	91,020
European (non-Finnish)	0.000678%	147,405

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.Ala74Val
Coding: c.221C>T
MANE Select: NM_024658
dbSNP: rs369567721
Type: single nucleotide variant
Location: chr14:24188359 (GRCh38)
Gene constraint: LOEUF 0.803 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.05 · 4 PDB
Residue 74: the importin n-terminal domain; a turn

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

Similar variants

IPO4 p.Arg20Cys Benign ★★ ⚠ same type
IPO4 p.Pro494Thr 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

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-ala74val (accessed [today's date]).

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