# NM_001202.6(BMP4):c.272C>G (p.Ser91Cys)

https://sugi.bio/variant/bmp4-p-ser91cys

## Summary

**BMP4 p.Ser91Cys (c.272C>G)** is classified **Conflicting classifications of pathogenicity** in BMP4 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.2796); Ultra-rare (popmax 0.0332%, nfe); Associated with orofacial cleft 11.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs121912767 · 8 submitters · 3 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.0332%, nfe)

## For patients & families {#patients}

This is a change in the BMP4 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 8 submitters, and is linked to orofacial cleft 11.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0018303/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BMP4](https://sugi.bio/atlas/gene/BMP4/) |
| Protein change (HGVS p.) | p.Ser91Cys |
| Coding change (HGVS c.) | c.272C>G |
| MANE Select transcript | [NM_001202](https://www.ncbi.nlm.nih.gov/nuccore/NM_001202) |
| dbSNP | [rs121912767](https://www.ncbi.nlm.nih.gov/snp/rs121912767/) |
| Variant type | single nucleotide variant |
| Location | chr14:53951951-53951951 (GRCh38) |
| ClinVar | [VCV17703](https://www.ncbi.nlm.nih.gov/clinvar/variation/17703/) |

**All HGVS expressions:** `NC_000014.8:g.54418669G>C`, `NC_000014.9:g.53951951G>C`, `NG_009215.1:g.9886C>G`, `NM_001202.6:c.272C>G`, `NM_001347912.1:c.413C>G`, `NM_001347913.2:c.83C>G`, `NM_001347914.2:c.272C>G`, `NM_001347915.2:c.83C>G`, `NM_001347916.1:c.272C>G`, `NM_001347917.1:c.83C>G`, `NM_130850.5:c.272C>G`, `NM_130851.4:c.272C>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.2796)
- REVEL 0.702 (pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -11.422 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** REVEL and SaProt call this damaging; AlphaMissense does not
- Conservation: phyloP 11.881, GERP 2.62, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 33.0**. 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 0.87** across the covering region of the MANE Select transcript (53,950,634–53,952,222), spanning 1,588 bp. Chi-square p 0.035. 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 (gnomAD v4.1): grpmax **0.0332%** (nfe) · FAF95 0.0304% · FAF99 0.0294% · 392/1,180,018 in the highest group · 405/1,609,808 alleles overall — ultra-rare (popmax 0.0332%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0332% | 3,010 |
| Remaining individuals (not grpmax-eligible) | 0.0112% | 8,922 |
| Finnish (not grpmax-eligible) | 0.00669% | 14,957 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,608 |
| East Asian | 0.00223% | 44,882 |

*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}

**BMP4** population constraint: LOEUF 0.258, pLI 0.99998, missense-Z 1.7532; 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):

- **BMP4-related ocular growth disorder** — Definitive (AD)

## Protein context {#protein}

Residue **91** lies in a UniProt-annotated variant site (in ofc11; also found in renal hypodysplasia patients); a modified residue (phosphoserine; by fam20c).

AlphaFold model confidence (whole protein): pLDDT 79.12, 47% of residues very-high.

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

*Describes the biological roles of BMP4 (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:** BMP4's established molecular role includes cytokine activity.


### Pathways affected {#pathways}

BMP4 participates in **11 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Molecules associated with elastic fibres](https://reactome.org/content/detail/R-HSA-2129379) | curated |
| [Post-translational protein phosphorylation](https://reactome.org/content/detail/R-HSA-8957275) | curated |
| [Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)](https://reactome.org/content/detail/R-HSA-381426) | curated |
| [Specification of primordial germ cells](https://reactome.org/content/detail/R-HSA-9827857) | curated |
| [Formation of intermediate mesoderm](https://reactome.org/content/detail/R-HSA-9761174) | electronic |
| [Formation of lateral plate mesoderm](https://reactome.org/content/detail/R-HSA-9758920) | electronic |
| [Formation of paraxial mesoderm](https://reactome.org/content/detail/R-HSA-9793380) | electronic |
| [Formation of the nephric duct](https://reactome.org/content/detail/R-HSA-9830364) | electronic |
| [Formation of the ureteric bud](https://reactome.org/content/detail/R-HSA-9830674) | electronic |
| [Germ layer formation at gastrulation](https://reactome.org/content/detail/R-HSA-9754189) | electronic |
| [Specification of the neural plate border](https://reactome.org/content/detail/R-HSA-9834899) | electronic |

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

**Molecular function:** cytokine activity, co-receptor binding, chemoattractant activity, BMP receptor binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, osteoblast differentiation, ureteric bud development, branching involved in ureteric bud morphogenesis, kidney development, mesonephros development.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-01-26.

**Submitter consensus:** conflicting (3 Uncertain significance, 3 Likely benign, 1 Pathogenic, 1 Benign).

**Submission history:** 8 submissions (2009–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2009-03-01 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Uncertain significance | criteria provided, single submitter | research | 2021-08-12 |
| Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-07-22 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2024-12-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-11 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2017-12-19 |
| Centre for Mendelian Genomics, University Medical Centre Ljubljana | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-11-25 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-26 |

## Associated conditions {#conditions}

[orofacial cleft 11](https://sugi.bio/atlas/disease/orofacial-cleft-11/), [intellectual disability](https://sugi.bio/atlas/disease/intellectual-disability/), [microphthalmia with brain and digit anomalies](https://sugi.bio/atlas/disease/microphthalmia-with-brain-and-digit-anomalies/).

**Reported phenotype names (ClinVar):** Orofacial cleft 11, Microphthalmia with brain and digit anomalies, not provided, Intellectual disability, not specified, CLEFT LIP WITH OR WITHOUT CLEFT PALATE, NONSYNDROMIC, 11, Orofacial cleft 11; ofc11, Microphthalmia, syndromic 6, MICROPHTHALMIA AND PITUITARY ANOMALIES, AllHighlyPenetrant.

## Similar variants {#similar}

Related BMP4 variant pages (same residue, condition, or type): [BMP4 p.Arg198Ter](/variant/bmp4-p-arg198ter), [BMP4 p.Arg113Gln](/variant/bmp4-p-arg113gln), [BMP4 p.Arg159Trp](/variant/bmp4-p-arg159trp), [BMP4 p.Arg162Trp](/variant/bmp4-p-arg162trp), [BMP4 p.Arg177His](/variant/bmp4-p-arg177his), [BMP4 p.Arg211Gln](/variant/bmp4-p-arg211gln), [BMP4 p.Arg223His](/variant/bmp4-p-arg223his), [BMP4 p.Arg245Trp](/variant/bmp4-p-arg245trp).

### 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 17703). 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.*