Is ALX4 p.Leu293= (c.879C>T) pathogenic?

ALX4 p.Leu293= (c.879C>T) is classified Benign in ALX4 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-01). Common (popmax 15%, eas) — too common for a highly-penetrant pathogenic allele; Associated with parietal foramina 2.

What condition is associated with ALX4 p.Leu293= (c.879C>T)?

ALX4 p.Leu293= (c.879C>T) is associated with parietal foramina 2 (ClinVar).

ALX4 p.Leu293=

Q: How common is ALX4 p.Leu293= (c.879C>T) in the general population?

ALX4 p.Leu293= (c.879C>T) is common (popmax 15%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.879C>T · rs12419361 · VCV304702

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Common

common (popmax 15%, eas) — too common for a highly-penetrant pathogenic allele

Conditions

parietal foramina 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.74	GERP -4.2, phastCons 1
Overall
CADD	5.798	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 15% East Asian · 6,740/44,854 alleles

Filtering AF 14.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 14.6%

Overall 10.6% 170,628/1,613,974 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	15%	7
Finnishnot grpmax-eligible	14.9%	7
Ashkenazi Jewishnot grpmax-eligible	14%	7
South Asian	13.6%	7
Middle Eastern	12.8%	8
Remaining individualsnot grpmax-eligible	10.6%	9
Admixed American	10.4%	10
European (non-Finnish)	10.2%	10
Amishnot grpmax-eligible	7.24%	14
African / African-American	5.5%	18

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.Leu293=
Coding: c.879C>T
MANE Select: NM_021926
dbSNP: rs12419361
Type: single nucleotide variant
Location: chr11:44267521 (GRCh38)
Gene constraint: LOEUF 0.902 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.00 · 4 PDB

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

Disease context

parietal foramina 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ALX4 c.*2991G>A Uncertain significance ★★ same condition
ALX4 p.Arg388His Uncertain significance ★★ ⚠ same condition
ALX4 p.Pro116Arg Uncertain significance ★★ ⚠ same condition
ALX4 p.Pro190Leu Uncertain significance ★★ ⚠ same condition
ALX4 p.Pro92Arg Uncertain significance ★★ ⚠ same condition
ALX4 p.Ser207Leu Uncertain significance ★★ ⚠ same condition
ALX4 c.467-45T>C Benign ★★ same condition
ALX4 c.778-117T>C Benign ★★ 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-leu293 (accessed [today's date]).

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