Is IPO8 p.Ala502Val (c.1505C>T) pathogenic?

IPO8 p.Ala502Val (c.1505C>T) is classified Uncertain significance in IPO8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-26). AlphaMissense: likely benign (0.1136); Ultra-rare (popmax 0.0121%, nfe); Associated with Inborn genetic diseases.

What condition is associated with IPO8 p.Ala502Val (c.1505C>T)?

IPO8 p.Ala502Val (c.1505C>T) is associated with Inborn genetic diseases (ClinVar).

How common is IPO8 p.Ala502Val (c.1505C>T) in the general population?

IPO8 p.Ala502Val (c.1505C>T) is ultra-rare (popmax 0.0121%, nfe) (gnomAD).

What do computational predictors say about IPO8 p.Ala502Val (c.1505C>T)?

AlphaMissense predicts likely benign (score 0.1136) — an in-silico prediction, not a clinical call.

IPO8 p.Ala502Val

c.1505C>T · rs749430025 · VCV2461164

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1136 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1136	likely benign
REVEL	0.1	moderately benign-leaning
SaProt	LLR -5.30	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.6	GERP 2.2, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 54 kb · p 1.3e-11 · regional, not allelic
Overall
CADD	19.26	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 0.0121% European (non-Finnish) · 143/1,179,732 alleles

Filtering AF 0.0105% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00981%

Overall 0.00948% 153/1,613,270 alleles · ultra-rare exomes 147/1,461,178 · genomes 6/152,092 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0121%	8,250
Remaining individualsnot grpmax-eligible	0.00801%	12,490
African / African-American	0.00401%	24,957
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,598
South Asian	0.0011%	91,026

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.Ala502Val
Coding: c.1505C>T
MANE Select: NM_006390
dbSNP: rs749430025
Type: single nucleotide variant
Location: chr12:30663578 (GRCh38)
Gene constraint: LOEUF 0.575 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 87.59
Residue 502: 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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

IPO8 p.Ala877Asp Uncertain significance ★★ ⚠ same condition
IPO8 p.Ala941Val Uncertain significance ★★ ⚠ same condition
IPO8 p.Arg1002Trp Uncertain significance ★★ ⚠ same condition
IPO8 p.Arg884Gln Uncertain significance ★★ ⚠ same condition
IPO8 p.Asn953Asp Uncertain significance ★★ ⚠ same condition
IPO8 p.His435Arg Uncertain significance ★★ ⚠ same condition
IPO8 p.Lys533Asn Uncertain significance ★★ ⚠ same condition
IPO8 p.Pro423Leu Uncertain significance ★★ ⚠ same condition

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-ala502val (accessed [today's date]).

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