Is IPO8 p.Ser657Tyr (c.1970C>A) pathogenic?

IPO8 p.Ser657Tyr (c.1970C>A) is classified Uncertain significance in IPO8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-27). AlphaMissense: likely pathogenic (0.7403); Absent from gnomAD v4.1; Associated with IPO8-related disorder.

What condition is associated with IPO8 p.Ser657Tyr (c.1970C>A)?

IPO8 p.Ser657Tyr (c.1970C>A) is associated with IPO8-related disorder (ClinVar).

How common is IPO8 p.Ser657Tyr (c.1970C>A) in the general population?

IPO8 p.Ser657Tyr (c.1970C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about IPO8 p.Ser657Tyr (c.1970C>A)?

AlphaMissense predicts likely pathogenic (score 0.7403) — an in-silico prediction, not a clinical call.

IPO8 p.Ser657Tyr

c.1970C>A · rs2498003770 · VCV2633091

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7403 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

IPO8-related disorder

Computational evidence

Protein change
AlphaMissense	0.7403	likely pathogenic
REVEL	0.531	indeterminate
SaProt	LLR -10.95	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.9, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 54 kb · p 1.3e-11 · regional, not allelic
Overall
CADD	26.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: IPO8
Protein: p.Ser657Tyr
Coding: c.1970C>A
MANE Select: NM_006390
dbSNP: rs2498003770
Type: single nucleotide variant
Location: chr12:30653071 (GRCh38)
Gene constraint: LOEUF 0.575 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 87.59
Residue 657: 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 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
IPO8 p.Glu688Asp Uncertain significance ★ ⚠ same condition
IPO8 p.Phe82Ser 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-ser657tyr (accessed [today's date]).

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