Is ALX4 p.Arg265Ter (c.793C>T) pathogenic?

ALX4 p.Arg265Ter (c.793C>T) is classified Pathogenic in ALX4 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2022-05-31). Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ALX4 p.Arg265Ter (c.793C>T)?

ALX4 p.Arg265Ter (c.793C>T) is associated with Inborn genetic diseases, frontonasal dysplasia with alopecia and genital anomaly, craniosynostosis 5, susceptibility to (ClinVar).

How common is ALX4 p.Arg265Ter (c.793C>T) in the general population?

ALX4 p.Arg265Ter (c.793C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

ALX4 p.Arg265Ter

c.793C>T · rs267606653 · VCV5020

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 3 of 4
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 0.95, phastCons 1
Overall
CADD	46.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,010 alleles

Overall 6.84e-05% 1/1,461,872 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.Arg265Ter
Coding: c.793C>T
MANE Select: NM_021926
dbSNP: rs267606653
Type: single nucleotide variant
Location: chr11:44267607 (GRCh38)
Gene constraint: LOEUF 0.902 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.00 · 4 PDB
Residue 265: a DNA-binding region; an α-helix

Full ALX4 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

Also linked: frontonasal dysplasia with alopecia and genital anomaly craniosynostosis 5, susceptibility to

Similar variants

ALX4 p.Arg193Gln Uncertain significance ★★ ⚠ same condition
ALX4 p.Arg257His Uncertain significance ★★ ⚠ same condition
ALX4 p.Arg388His Uncertain significance ★★ ⚠ same condition
ALX4 p.Asp176Gly Uncertain significance ★★ ⚠ same condition
ALX4 p.Asp206Asn Uncertain significance ★★ ⚠ same condition
ALX4 p.Asp326Asn Uncertain significance ★★ ⚠ same condition
ALX4 p.Cys331Tyr Uncertain significance ★★ ⚠ same condition
ALX4 p.Gln104Pro 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/alx4-p-arg265ter (accessed [today's date]).

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