Is ALX4 p.Pro306= (c.918G>A) pathogenic?

ALX4 p.Pro306= (c.918G>A) is classified Benign in ALX4 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-30). Low-frequency (popmax 2.54%, afr); Associated with parietal foramina 2.

What condition is associated with ALX4 p.Pro306= (c.918G>A)?

ALX4 p.Pro306= (c.918G>A) is associated with parietal foramina 2 (ClinVar).

How common is ALX4 p.Pro306= (c.918G>A) in the general population?

ALX4 p.Pro306= (c.918G>A) is low-frequency (popmax 2.54%, afr) (gnomAD).

ALX4 p.Pro306=

c.918G>A · rs145904583 · VCV710007

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.54%, afr)

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 -20	GERP -3.6
Overall
CADD	1.961	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.54% African / African-American · 1,906/74,914 alleles

Filtering AF 2.45% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.41%

Overall 0.146% 2,336/1,603,294 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.54%	39
Middle Eastern	0.185%	541
Admixed American	0.18%	557
Remaining individualsnot grpmax-eligible	0.161%	620
South Asian	0.0244%	4,092
European (non-Finnish)	0.0159%	6,276
East Asian	0.00673%	14,865

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.Pro306=
Coding: c.918G>A
MANE Select: NM_021926
dbSNP: rs145904583
Type: single nucleotide variant
Location: chr11:44265172 (GRCh38)
Gene constraint: LOEUF 0.902 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.00 · 4 PDB
Residue 306: a UniProt-annotated variant site (in)

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 p.Pro306Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-pro306 (accessed [today's date]).

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