# NM_006147.4(IRF6):c.827T>C (p.Phe276Ser)

https://sugi.bio/variant/irf6-p-phe276ser

## Summary

**IRF6 p.Phe276Ser (c.827T>C)** is classified **Likely pathogenic** in IRF6 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely pathogenic (0.9997); Absent from gnomAD v4.1; Associated with orofacial cleft 6, susceptibility to.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 3 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the IRF6 gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to orofacial cleft 6, susceptibility to.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [IRF6](https://sugi.bio/atlas/gene/IRF6/) |
| Protein change (HGVS p.) | p.Phe276Ser |
| Coding change (HGVS c.) | c.827T>C |
| MANE Select transcript | [NM_006147](https://www.ncbi.nlm.nih.gov/nuccore/NM_006147) |
| Variant type | single nucleotide variant |
| Location | chr1:209790728-209790728 (GRCh38) |
| ClinVar | [VCV3383146](https://www.ncbi.nlm.nih.gov/clinvar/variation/3383146/) |

**All HGVS expressions:** `NC_000001.10:g.209964073A>G`, `NC_000001.11:g.209790728A>G`, `NG_007081.2:g.20407T>C`, `NM_001206696.2:c.542T>C`, `NM_006147.4:c.827T>C`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9997) — concordant with the pathogenic call
- REVEL 0.95 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.904 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.23, GERP 2.85, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 4%** most-pathogenic-predicted substitutions in IRF6 (of 2,767 modeled).
- CADD: **PHRED 32.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.56** across the covering region of the MANE Select transcript (209,788,638–209,792,296), spanning 3,658 bp. Chi-square p 7.6e-11. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**IRF6** population constraint: LOEUF 0.214, pLI 1, missense-Z 3.8977; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **IRF6-related condition** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 74.19, 44% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of IRF6 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** IRF6's established molecular role includes sequence-specific DNA binding.


### Pathways affected {#pathways}

IRF6 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Interferon alpha/beta signaling](https://reactome.org/content/detail/R-HSA-909733) | curated |
| [Interferon gamma signaling](https://reactome.org/content/detail/R-HSA-877300) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** sequence-specific DNA binding, sequence-specific double-stranded DNA binding.

**Biological process:** negative regulation of cell population proliferation, positive regulation of transcription by RNA polymerase II.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Juno Genomics, Hangzhou Juno Genomics, Inc | Likely pathogenic | criteria provided, single submitter | clinical testing |  |

## Associated conditions {#conditions}

[orofacial cleft 6, susceptibility to](https://sugi.bio/atlas/disease/orofacial-cleft-6-susceptibility-to/), [van der Woude syndrome 1](https://sugi.bio/atlas/disease/van-der-woude-syndrome-1/), [autosomal dominant popliteal pterygium syndrome](https://sugi.bio/atlas/disease/autosomal-dominant-popliteal-pterygium-syndrome/).

**Reported phenotype names (ClinVar):** Orofacial cleft 6, susceptibility to, Autosomal dominant popliteal pterygium syndrome, Van der Woude syndrome 1, CLEFT LIP WITH OR WITHOUT CLEFT PALATE, NONSYNDROMIC, 6, CLEFT LIP AND/OR PALATE WITH MUCOUS CYSTS OF LOWER LIP, van der Woude Syndrome (VWS), CLEFT LIP/PALATE, PARAMEDIAN MUCOUS CYSTS OF THE LOWER LIP, POPLITEAL PTERYGIUM, DIGITAL AND GENITAL ANOMALIES, FACIOGENITOPOPLITEAL SYNDROME, Popliteal Pterygium Syndrome (PPS).

## Similar variants {#similar}

Related IRF6 variant pages (same residue, condition, or type): [IRF6 c.1060+1G>A](/variant/irf6-c-1060-plus-1g-a), [IRF6 p.Arg250Gln](/variant/irf6-p-arg250gln), [IRF6 p.Arg250Ter](/variant/irf6-p-arg250ter), [IRF6 p.Arg400Trp](/variant/irf6-p-arg400trp), [IRF6 p.Arg412Ter](/variant/irf6-p-arg412ter), [IRF6 p.Arg6Cys](/variant/irf6-p-arg6cys), [IRF6 p.Arg84Cys](/variant/irf6-p-arg84cys), [IRF6 p.Arg84His](/variant/irf6-p-arg84his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 3383146). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*