Is IRF6 p.Pro268= (c.804C>T) pathogenic?

IRF6 p.Pro268= (c.804C>T) is classified Likely benign in IRF6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-28). Ultra-rare (popmax 0.0245%, eas); Associated with van der Woude syndrome.

What condition is associated with IRF6 p.Pro268= (c.804C>T)?

IRF6 p.Pro268= (c.804C>T) is associated with van der Woude syndrome, orofacial cleft 6, susceptibility to, popliteal pterygium syndrome (ClinVar).

How common is IRF6 p.Pro268= (c.804C>T) in the general population?

IRF6 p.Pro268= (c.804C>T) is ultra-rare (popmax 0.0245%, eas) (gnomAD).

IRF6 p.Pro268=

c.804C>T · VCV4790922

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0245%, eas)

Conditions

van der Woude syndrome

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 -8.5	GERP -5.7
Overall
CADD	1.335	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0245% East Asian · 11/44,886 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.00161% 26/1,614,032 alleles · ultra-rare exomes 23/1,461,882 · genomes 3/152,150 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0245%	4,081
South Asian	0.00439%	22,769
European (non-Finnish)	0.000932%	107,276

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.Pro268=
Coding: c.804C>T
MANE Select: NM_006147
Type: single nucleotide variant
Location: chr1:209790751 (GRCh38)
Gene constraint: LOEUF 0.214 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.19

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

Disease context

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

Also linked: orofacial cleft 6, susceptibility to popliteal pterygium 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-pro268 (accessed [today's date]).

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