Is IPO7 p.Tyr136Cys (c.407A>G) pathogenic?

IPO7 p.Tyr136Cys (c.407A>G) is classified Uncertain significance in IPO7 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-07). AlphaMissense: ambiguous (0.3576); Ultra-rare (popmax 0.0119%, amr).

How common is IPO7 p.Tyr136Cys (c.407A>G) in the general population?

IPO7 p.Tyr136Cys (c.407A>G) is ultra-rare (popmax 0.0119%, amr) (gnomAD).

What do computational predictors say about IPO7 p.Tyr136Cys (c.407A>G)?

AlphaMissense predicts ambiguous (score 0.3576) — an in-silico prediction, not a clinical call.

IPO7 p.Tyr136Cys

c.407A>G · VCV4276188

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3576 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0119%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3576	ambiguous
REVEL	0.687	pathogenic-leaning
SaProt	LLR -8.53	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.6, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 15 kb · p 0.24 · regional, not allelic
Overall
CADD	29.1	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 0.0119% Admixed American · 7/58,856 alleles

Filtering AF 0.00553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00386%

Overall 0.000498% 8/1,607,678 alleles · ultra-rare exomes 8/1,455,538 · genomes 0/152,140 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0119%	8,408
Remaining individualsnot grpmax-eligible	0.00161%	62,176

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: IPO7
Protein: p.Tyr136Cys
Coding: c.407A>G
MANE Select: NM_006391
Type: single nucleotide variant
Location: chr11:9410014 (GRCh38)
Gene constraint: LOEUF 0.138 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 88.24

Full IPO7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

IPO7 p.Tyr136Asn Uncertain significance ★ ⚠ same residue
IPO7 p.Ala363Gly Uncertain significance ★ ⚠ same type
IPO7 p.Ala74Ser Uncertain significance ★ ⚠ same type
IPO7 p.Ala764Gly Uncertain significance ★ ⚠ same type
IPO7 p.Ala786Gly Uncertain significance ★ ⚠ same type
IPO7 p.Ala843Ser Uncertain significance ★ ⚠ same type
IPO7 p.Ala923Gly Uncertain significance ★ ⚠ same type
IPO7 p.Ala979Thr 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/ipo7-p-tyr136cys (accessed [today's date]).

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