# NM_001111067.4(ACVR1):c.103T>C (p.Cys35Arg)

https://sugi.bio/variant/acvr1-p-cys35arg

## Summary

**ACVR1 p.Cys35Arg (c.103T>C)** is classified **Uncertain significance** in ACVR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: likely pathogenic (0.9988); Very rare (popmax 8.47e-05%, nfe); Associated with fibrodysplasia ossificans progressiva.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the ACVR1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to fibrodysplasia ossificans progressiva.

*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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Not applicable |
| Age of onset (of this condition) | Childhood |
| Prevalence | <1 / 1 000 000 (Worldwide) |
| Clinical trials | 23 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ACVR1 is a diagnostic-grade gene on 3 Genomics England panels |

**Commonly reported features of Fibrodysplasia ossificans progressiva** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Ectopic ossification — Obligate (100%)
- Limitation of joint mobility — Very frequent (99-80%)
- Subcutaneous nodule — Very frequent (99-80%)
- Abnormal hallux morphology — Very frequent (99-80%)
- Fused cervical vertebrae — Very frequent (99-80%)
- Spinal rigidity — Very frequent (99-80%)
- Abnormal vertebral morphology — Very frequent (99-80%)
- Abnormality of the first metatarsal bone — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006445/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ACVR1](https://sugi.bio/atlas/gene/ACVR1/) |
| Protein change (HGVS p.) | p.Cys35Arg |
| Coding change (HGVS c.) | c.103T>C |
| MANE Select transcript | [NM_001111067](https://www.ncbi.nlm.nih.gov/nuccore/NM_001111067) |
| Variant type | single nucleotide variant |
| Location | chr2:157780565-157780565 (GRCh38) |
| ClinVar | [VCV4278067](https://www.ncbi.nlm.nih.gov/clinvar/variation/4278067/) |

**All HGVS expressions:** `NC_000002.11:g.158637077A>G`, `NC_000002.12:g.157780565A>G`, `NG_008004.1:g.99547T>C`, `NM_001105.5:c.103T>C`, `NM_001111067.4:c.103T>C`, `NM_001347663.1:c.103T>C`, `NM_001347664.1:c.103T>C`, `NM_001347665.1:c.103T>C`, `NM_001347666.1:c.103T>C`, `NM_001347667.2:c.103T>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9988)
- REVEL 0.971 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -18.48 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.112, GERP 1.92, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 6%** most-pathogenic-predicted substitutions in ACVR1 (of 2,986 modeled).
- CADD: **PHRED 28.0**. 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 0.86** across the covering region of the MANE Select transcript (157,774,168–157,799,493), spanning 25,325 bp. Chi-square p 0.034. 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 **8.47e-05%** (nfe) · 1/1,179,968 in the highest group · 1/1,461,884 alleles overall — very rare (popmax 8.47e-05%, nfe).

*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}

**ACVR1** population constraint: LOEUF 0.835, pLI 2.4131e-08, missense-Z 2.9548. *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):

- **fibrodysplasia ossificans progressiva** — Definitive (AD)
- **congenital heart disease** — Limited (AD)

## Protein context {#protein}

Residue **35** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 83.70, 58% of residues very-high.

**85 experimental structure(s)** (PDB): [3H9R](https://www.rcsb.org/structure/3H9R), [3MTF](https://www.rcsb.org/structure/3MTF), [3OOM](https://www.rcsb.org/structure/3OOM), [3Q4U](https://www.rcsb.org/structure/3Q4U), [4BGG](https://www.rcsb.org/structure/4BGG), [4C02](https://www.rcsb.org/structure/4C02) — incl. mutant structure 6EIX.

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

*Describes the biological roles of ACVR1 (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:** ACVR1's established molecular role includes protein kinase activity.


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

**Molecular function:** protein kinase activity, protein serine/threonine kinase activity, transmembrane receptor protein serine/threonine kinase activity, ATP binding, activin receptor activity, type I, protein homodimerization activity.

**Biological process:** osteoblast differentiation, embryonic heart tube morphogenesis, mitral valve morphogenesis, atrial septum primum morphogenesis, transforming growth factor beta receptor signaling pathway, negative regulation of signal transduction.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-09-10.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-09-10 |

## Associated conditions {#conditions}

[fibrodysplasia ossificans progressiva](https://sugi.bio/atlas/disease/fibrodysplasia-ossificans-progressiva/).

**Reported phenotype names (ClinVar):** Progressive myositis ossificans, Fibrodysplasia Ossificans Progressiva, Progressive ossifying myositis, Myositis ossificans progressiva.

## Similar variants {#similar}

Related ACVR1 variant pages (same residue, condition, or type): [ACVR1 p.Arg206His](/variant/acvr1-p-arg206his), [ACVR1 p.Gly328Glu](/variant/acvr1-p-gly328glu), [ACVR1 p.Gly356Asp](/variant/acvr1-p-gly356asp), [ACVR1 p.Ser41Phe](/variant/acvr1-p-ser41phe), [ACVR1 c.1395+5G>A](/variant/acvr1-c-1395-plus-5g-a), [ACVR1 c.643+7C>T](/variant/acvr1-c-643-plus-7c-t), [ACVR1 c.644-3T>C](/variant/acvr1-c-644-minus-3t-c), [ACVR1 c.68-25T>C](/variant/acvr1-c-68-minus-25t-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 4278067). 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.*