Is IRF6 p.Asp296= (c.888C>T) pathogenic?

IRF6 p.Asp296= (c.888C>T) is classified Conflicting classifications of pathogenicity in IRF6 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-03-04). Ultra-rare (popmax 0.0164%, mid); Associated with van der Woude syndrome 1.

What condition is associated with IRF6 p.Asp296= (c.888C>T)?

IRF6 p.Asp296= (c.888C>T) is associated with van der Woude syndrome 1, orofacial cleft 6, susceptibility to, popliteal pterygium syndrome (ClinVar).

How common is IRF6 p.Asp296= (c.888C>T) in the general population?

IRF6 p.Asp296= (c.888C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

IRF6 p.Asp296=

c.888C>T · rs748882482 · VCV873581

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

van der Woude syndrome 1

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 -5.6	GERP -5.7
Overall
CADD	1.22	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00198% 32/1,614,110 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.008%	12,498
Admixed American	0.00667%	15,002
South Asian	0.00329%	30,365
European (non-Finnish)	0.00161%	62,108

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: IRF6
Protein: p.Asp296=
Coding: c.888C>T
MANE Select: NM_006147
dbSNP: rs748882482
Type: single nucleotide variant
Location: chr1:209790667 (GRCh38)
Gene constraint: LOEUF 0.214 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.19
Residue 296: a UniProt-annotated variant site (in vws1)

Full IRF6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

van der Woude syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: orofacial cleft 6, susceptibility to popliteal pterygium syndrome van der Woude syndrome

Similar variants

IRF6 c.1060+1G>A Pathogenic/Likely pathogenic ★★ same condition
IRF6 p.Arg250Gln Pathogenic/Likely pathogenic ★★ same condition
IRF6 p.Arg250Ter Pathogenic ★★ same condition
IRF6 p.Arg400Trp Pathogenic ★★ same condition
IRF6 p.Arg412Ter Pathogenic ★★ same condition
IRF6 p.Arg6Cys Pathogenic/Likely pathogenic ★★ same condition
IRF6 p.Arg84Cys Pathogenic/Likely pathogenic ★★ same condition
IRF6 p.Arg84His Pathogenic ★★ 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/irf6-p-asp296 (accessed [today's date]).

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