Is ALX4 p.Pro97= (c.291G>A) pathogenic?

ALX4 p.Pro97= (c.291G>A) is classified Uncertain significance in ALX4 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-04-27). Very rare (popmax 0.00951%, sas); Associated with parietal foramina 2.

What condition is associated with ALX4 p.Pro97= (c.291G>A)?

ALX4 p.Pro97= (c.291G>A) is associated with parietal foramina 2 (ClinVar).

How common is ALX4 p.Pro97= (c.291G>A) in the general population?

ALX4 p.Pro97= (c.291G>A) is very rare (popmax 0.00951%, sas) (gnomAD).

ALX4 p.Pro97=

c.291G>A · rs767580968 · VCV879087

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00951%, sas)

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 0.083	GERP -2.1, phastCons 0.97
Overall
CADD	10.89	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00951% South Asian · 8/84,096 alleles

Filtering AF 0.00468% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00345%

Overall 0.00349% 54/1,545,792 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00951%	10,512
European (non-Finnish)	0.00376%	26,616
Remaining individualsnot grpmax-eligible	0.00334%	29,902
Admixed American	0.00196%	50,956

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.Pro97=
Coding: c.291G>A
MANE Select: NM_021926
dbSNP: rs767580968
Type: single nucleotide variant
Location: chr11:44309772 (GRCh38)
Gene constraint: LOEUF 0.902 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.00 · 4 PDB
Residue 97: the 'disordered' region

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-pro97 (accessed [today's date]).

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