Is IPO8 p.Ala941Val (c.2822C>T) pathogenic?

IPO8 p.Ala941Val (c.2822C>T) is classified Uncertain significance in IPO8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.1179); Rare (popmax 0.105%, nfe); Associated with Inborn genetic diseases.

What condition is associated with IPO8 p.Ala941Val (c.2822C>T)?

IPO8 p.Ala941Val (c.2822C>T) is associated with Inborn genetic diseases (ClinVar).

How common is IPO8 p.Ala941Val (c.2822C>T) in the general population?

IPO8 p.Ala941Val (c.2822C>T) is rare (popmax 0.105%, nfe) (gnomAD).

What do computational predictors say about IPO8 p.Ala941Val (c.2822C>T)?

AlphaMissense predicts likely benign (score 0.1179) — an in-silico prediction, not a clinical call.

IPO8 p.Ala941Val

c.2822C>T · rs150350956 · VCV3110351

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1179 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.105%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1179	likely benign
REVEL	0.375	indeterminate
SaProt	LLR -4.52	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 54 kb · p 1.3e-11 · regional, not allelic
Overall
CADD	27.0	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 0.105% European (non-Finnish) · 1,243/1,179,900 alleles

Filtering AF 0.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0985%

Overall 0.0845% 1,363/1,613,838 alleles · rare exomes 1,272/1,461,714 · genomes 91/152,124 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.105%	949
Remaining individualsnot grpmax-eligible	0.0944%	1,059
Admixed American	0.0533%	1,875
Ashkenazi Jewishnot grpmax-eligible	0.0338%	2,960
African / African-American	0.024%	4,161
East Asian	0.00223%	44,874

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.Ala941Val
Coding: c.2822C>T
MANE Select: NM_006390
dbSNP: rs150350956
Type: single nucleotide variant
Location: chr12:30634160 (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

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

Similar variants

IPO8 p.Ala941Ser Uncertain significance ★ ⚠ same residue
IPO8 p.Ala941= Likely benign same residue
IPO8 p.Ala877Asp 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

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-ala941val (accessed [today's date]).

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