Is IPO11 p.Pro229Ala (c.685C>G) pathogenic?

IPO11 p.Pro229Ala (c.685C>G) is classified Uncertain significance in IPO11 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-30). AlphaMissense: ambiguous (0.4357); Very rare (popmax 0.00333%, amr).

How common is IPO11 p.Pro229Ala (c.685C>G) in the general population?

IPO11 p.Pro229Ala (c.685C>G) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about IPO11 p.Pro229Ala (c.685C>G)?

AlphaMissense predicts ambiguous (score 0.4357) — an in-silico prediction, not a clinical call.

IPO11 p.Pro229Ala

c.685C>G · rs1336545451 · VCV3110305

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4357 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4357	ambiguous
REVEL	0.273	benign-leaning
SaProt	LLR -7.57	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.6, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 48 kb · p 0.2 · regional, not allelic
Overall
CADD	21.9	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 0.00333% Admixed American · 2/59,984 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000124% 2/1,613,628 alleles · very rare exomes 1/1,461,466 · genomes 1/152,162 · joint denominator

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: IPO11
Protein: p.Pro229Ala
Coding: c.685C>G
MANE Select: NM_016338
dbSNP: rs1336545451
Type: single nucleotide variant
Location: chr5:62470285 (GRCh38)
Gene constraint: LOEUF 0.598 · pLI 0.10 (gnomAD)
Structure: AlphaFold pLDDT 93.53

Full IPO11 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

LRRC70 p.Ser229Arg Uncertain significance ★ ⚠ same residue
IPO11 p.Thr409Ala Uncertain significance ★★ ⚠ same type
IPO11 p.Ala726= Benign ★★ same type
IPO11 p.Asn260Asp Benign ★★ same type
IPO11 p.Leu112= Benign ★★ same type
IPO11 p.Leu246= Benign ★★ same type
IPO11 p.Leu799= Benign ★★ same type
IPO11 p.Ala110Val 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/ipo11-p-pro229ala (accessed [today's date]).

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