Is IPO8 p.Val499Ile (c.1495G>A) pathogenic?

IPO8 p.Val499Ile (c.1495G>A) is classified Likely benign in IPO8 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-07-26). AlphaMissense: likely benign (0.0945); Rare (popmax 0.212%, afr).

How common is IPO8 p.Val499Ile (c.1495G>A) in the general population?

IPO8 p.Val499Ile (c.1495G>A) is rare (popmax 0.212%, afr) (gnomAD).

What do computational predictors say about IPO8 p.Val499Ile (c.1495G>A)?

AlphaMissense predicts likely benign (score 0.0945) — an in-silico prediction, not a clinical call.

IPO8 p.Val499Ile

c.1495G>A · rs141041651 · VCV715646

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0945 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.212%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0945	likely benign
REVEL	0.071	moderately benign-leaning
SaProt	LLR -6.76	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 2.3	GERP -2.2, phastCons 0.98
Regional constraint	o/e 0.80	unconstrained · MANE · 54 kb · p 1.3e-11 · regional, not allelic
Overall
CADD	21.8	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 0.212% African / African-American · 159/75,036 alleles

Filtering AF 0.185% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.175%

Overall 0.0125% 202/1,613,490 alleles · rare exomes 130/1,461,178 · genomes 72/152,312 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.212%	472
Middle Eastern	0.0495%	2,020
Remaining individualsnot grpmax-eligible	0.0176%	5,681
Admixed American	0.015%	6,667
Finnishnot grpmax-eligible	0.0126%	7,960
East Asian	0.00223%	44,864
South Asian	0.0022%	45,518
European (non-Finnish)	0.000763%	131,089

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: IPO8
Protein: p.Val499Ile
Coding: c.1495G>A
MANE Select: NM_006390
dbSNP: rs141041651
Type: single nucleotide variant
Location: chr12:30663588 (GRCh38)
Gene constraint: LOEUF 0.575 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 87.59
Residue 499: a UniProt-annotated variant site (in viss; undetectable protein levels in either patient's fibroblasts or patient's epstein-barr virus-immortalized b cell lines); a UniProt-annotated variant site (in viss); a UniProt-annotated variant site (in viss; undetectable protein levels in patient's fibroblasts, although mrna levels seem unaffected)

Full IPO8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IPO8 c.2900-1G>A Pathogenic/Likely pathogenic ★★ same type
IPO8 p.Arg474Ter Pathogenic ★★ same type
IPO8 p.Arg803Ter Pathogenic/Likely pathogenic ★★ same type
IPO8 p.Trp259Ter Pathogenic ★★ same type
IPO8 p.Ala877Asp Uncertain significance ★★ ⚠ same type
IPO8 p.Ala941Val Uncertain significance ★★ ⚠ same type
IPO8 p.Arg1002Trp Uncertain significance ★★ ⚠ same type
IPO8 p.Arg884Gln 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/ipo8-p-val499ile (accessed [today's date]).

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