Is ALX4 p.Pro133fs (c.398del) pathogenic?

ALX4 p.Pro133fs (c.398del) is classified Likely pathogenic in ALX4 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-04-14). Very rare (popmax 0.00017%, nfe).

How common is ALX4 p.Pro133fs (c.398del) in the general population?

ALX4 p.Pro133fs (c.398del) is very rare (popmax 0.00017%, nfe) (gnomAD).

ALX4 p.Pro133fs

c.398del · rs1085307637 · VCV426461

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 1 of 4
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2	GERP 0.23, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,174,280 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000139% 2/1,440,048 alleles · very rare

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: ALX4
Protein: p.Pro133fs
Coding: c.398del
MANE Select: NM_021926
dbSNP: rs1085307637
Type: Deletion
Location: chr11:44309665 (GRCh38)
Gene constraint: LOEUF 0.902 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.00 · 4 PDB
Residue 133: the 'disordered' region

Full ALX4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ALX4 p.Gly85fs Pathogenic/Likely pathogenic ★★ same type
ALX4 p.Gln109_Gln115del Uncertain significance ★★ same type
ALX4 c.778del Likely pathogenic ★ same type
ALX4 p.Gly340fs Likely pathogenic ★ same type
ALX4 p.Leu226fs Likely pathogenic ★ same type
ALX4 c.*190del Likely benign ★ same type
ALX4 p.Asp169fs Pathogenic same type
ALX4 p.Cys129fs Pathogenic 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/alx4-p-pro133fs (accessed [today's date]).

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