Is IRF6 p.Ser307= (c.921C>T) pathogenic?

IRF6 p.Ser307= (c.921C>T) is classified Conflicting classifications of pathogenicity in IRF6 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-04-01). Very rare (popmax 0.005%, amr); Associated with van der Woude syndrome.

What condition is associated with IRF6 p.Ser307= (c.921C>T)?

IRF6 p.Ser307= (c.921C>T) is associated with van der Woude syndrome, orofacial cleft 6, susceptibility to, popliteal pterygium syndrome (ClinVar).

How common is IRF6 p.Ser307= (c.921C>T) in the general population?

IRF6 p.Ser307= (c.921C>T) is very rare (popmax 0.005%, amr) (gnomAD).

IRF6 p.Ser307=

c.921C>T · rs750815592 · VCV1409081

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Conditions

van der Woude syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.54	donor gain · deltas
Pangolin	Δ0.47	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.9	GERP -0.009, phastCons 1
Overall
CADD	20.6	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/59,998 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000434% 7/1,614,086 alleles · very rare exomes 7/1,461,894 · genomes 0/152,192 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,999
East Asian	0.00223%	44,904
European (non-Finnish)	0.000254%	393,348

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.Ser307=
Coding: c.921C>T
MANE Select: NM_006147
dbSNP: rs750815592
Type: single nucleotide variant
Location: chr1:209790634 (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-ser307 (accessed [today's date]).

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