Is ALX4 p.Pro23= (c.69G>C) pathogenic?

ALX4 p.Pro23= (c.69G>C) is classified Benign in ALX4 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-20). Common (popmax 8.16%, sas) — too common for a highly-penetrant pathogenic allele; Associated with frontonasal dysplasia with alopecia and genital anomaly.

What condition is associated with ALX4 p.Pro23= (c.69G>C)?

ALX4 p.Pro23= (c.69G>C) is associated with frontonasal dysplasia with alopecia and genital anomaly, parietal foramina 2, craniosynostosis 5, susceptibility to (ClinVar).

ALX4 p.Pro23=

Q: How common is ALX4 p.Pro23= (c.69G>C) in the general population?

ALX4 p.Pro23= (c.69G>C) is common (popmax 8.16%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.69G>C · rs115968657 · VCV304716

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 8.16%, sas) — too common for a highly-penetrant pathogenic allele

Conditions

frontonasal dysplasia with alopecia and genital anomaly

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 0.51	GERP -2.2, phastCons 1
Overall
CADD	13.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.16% South Asian · 7,242/88,752 alleles

Filtering AF 8% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.94%

Overall 0.806% 12,910/1,602,420 alleles · common

Ancestry group	Frequency	1 in
South Asiangrpmax	8.16%	12
Middle Eastern	0.991%	101
African / African-American	0.978%	102
Remaining individualsnot grpmax-eligible	0.932%	107
European (non-Finnish)	0.331%	302
Admixed American	0.275%	364
Finnishnot grpmax-eligible	0.229%	436
East Asian	0.178%	562
Ashkenazi Jewishnot grpmax-eligible	0.0785%	1,273

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.Pro23=
Coding: c.69G>C
MANE Select: NM_021926
dbSNP: rs115968657
Type: single nucleotide variant
Location: chr11:44309994 (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

frontonasal dysplasia with alopecia and genital anomaly — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: parietal foramina 2 craniosynostosis 5, susceptibility to

Similar variants

ALX4 p.Arg265Ter Pathogenic ★★ same condition
ALX4 c.*2991G>A Uncertain significance ★★ same condition
ALX4 p.Arg388His Uncertain significance ★★ ⚠ same condition
ALX4 p.Asp326Asn 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

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-pro23 (accessed [today's date]).

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