Is IPO8 p.Ala941= (c.2823G>A) pathogenic?

IPO8 p.Ala941= (c.2823G>A) is classified Likely benign in IPO8 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-06-29). Very rare (popmax 0.00551%, nfe); Associated with IPO8-related disorder.

What condition is associated with IPO8 p.Ala941= (c.2823G>A)?

IPO8 p.Ala941= (c.2823G>A) is associated with IPO8-related disorder (ClinVar).

How common is IPO8 p.Ala941= (c.2823G>A) in the general population?

IPO8 p.Ala941= (c.2823G>A) is very rare (popmax 0.00551%, nfe) (gnomAD).

IPO8 p.Ala941=

c.2823G>A · rs756381329 · VCV3054391

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00551%, nfe)

Conditions

IPO8-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.01	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.26	phastCons 0.91
Overall
CADD	9.986	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00551% European (non-Finnish) · 65/1,179,902 alleles

Filtering AF 0.00443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00403%

Overall 0.00477% 77/1,613,866 alleles · very rare exomes 74/1,461,720 · genomes 3/152,146 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0096%	10,413
European (non-Finnish)grpmax	0.00551%	18,152
Admixed American	0.005%	19,996
South Asian	0.0022%	45,538
African / African-American	0.00134%	74,906

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala941=
Coding: c.2823G>A
MANE Select: NM_006390
dbSNP: rs756381329
Type: single nucleotide variant
Location: chr12:30634159 (GRCh38)
Gene constraint: LOEUF 0.575 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 87.59
Residue 941: 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

IPO8-related disorder

Similar variants

IPO8 p.Ala941Val Uncertain significance ★★ ⚠ same residue
IPO8 p.Ala941Ser Uncertain significance ★ ⚠ same residue
IPO8 c.2900-1G>A Pathogenic/Likely pathogenic ★★ same condition
IPO8 p.Arg474Ter Pathogenic ★★ same condition
IPO8 p.Trp259Ter Pathogenic ★★ same condition
IPO8 c.1428+5G>A Pathogenic ★ same condition
IPO8 p.Arg971Ter Likely pathogenic ★ same condition
IPO8 p.Trp229Ter Pathogenic ★ 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-ala941 (accessed [today's date]).

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