Is IPO4 p.Leu995Val (c.2983T>G) pathogenic?

IPO4 p.Leu995Val (c.2983T>G) is classified Uncertain significance in IPO4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-17). AlphaMissense: likely benign (0.082); Very rare (popmax 8.48e-05%, nfe).

How common is IPO4 p.Leu995Val (c.2983T>G) in the general population?

IPO4 p.Leu995Val (c.2983T>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about IPO4 p.Leu995Val (c.2983T>G)?

AlphaMissense predicts likely benign (score 0.082) — an in-silico prediction, not a clinical call.

IPO4 p.Leu995Val

c.2983T>G · VCV3860948

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.082 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.082	likely benign
REVEL	0.045	moderately benign-leaning
SaProt	LLR -5.60	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 0.36	GERP -2.2, phastCons 0.88
Regional constraint	o/e 0.88	unconstrained · MANE · 3,885 bp · p 0.0022 · regional, not allelic
Overall
CADD	17.2	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 8.48e-05% European (non-Finnish) · 1/1,179,124 alleles

Overall 6.85e-05% 1/1,459,696 alleles · very rare

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.Leu995Val
Coding: c.2983T>G
MANE Select: NM_024658
Type: single nucleotide variant
Location: chr14:24181575 (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.Leu995Ser Uncertain significance ★ ⚠ same residue
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

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-leu995val (accessed [today's date]).

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