# NM_001111067.4(ACVR1):c.1188C>T (p.Phe396=)

https://sugi.bio/variant/acvr1-p-phe396

## Summary

**ACVR1 p.Phe396= (c.1188C>T)** is classified **Likely benign** in ACVR1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-05-07). Ultra-rare (popmax 0.0164%, mid).

**At a glance:** Likely benign · review: Multiple submitters · 3 submitters · ultra-rare (popmax 0.0164%, mid)

## For patients & families {#patients}

This is a change in the ACVR1 gene that is classified as likely benign — not considered disease-causing, submitted by 3 submitters.

*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 | [ACVR1](https://sugi.bio/atlas/gene/ACVR1/) |
| Protein change (HGVS p.) | p.Phe396= |
| Coding change (HGVS c.) | c.1188C>T |
| MANE Select transcript | [NM_001111067](https://www.ncbi.nlm.nih.gov/nuccore/NM_001111067) |
| Variant type | single nucleotide variant |
| Location | chr2:157760956-157760956 (GRCh38) |
| ClinVar | [VCV4280855](https://www.ncbi.nlm.nih.gov/clinvar/variation/4280855/) |

**All HGVS expressions:** `NC_000002.11:g.158617468G>A`, `NC_000002.12:g.157760956G>A`, `NG_008004.1:g.119156C>T`, `NM_001105.5:c.1188C>T`, `NM_001111067.4:c.1188C>T`, `NM_001347663.1:c.1188C>T`, `NM_001347664.1:c.1188C>T`, `NM_001347665.1:c.1188C>T`, `NM_001347666.1:c.1188C>T`, `NM_001347667.2:c.1188C>T`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP -0.217, GERP -4.1, phastCons 0.001 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 11.78**. 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.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.20 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0164%** (mid) · FAF95 0.00255% · FAF99 0.00168% · 1/6,084 in the highest group · 43/1,613,954 alleles overall — ultra-rare (popmax 0.0164%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0164% | 6,084 |
| African / African-American | 0.00668% | 14,981 |
| Admixed American | 0.00333% | 29,996 |
| South Asian | 0.00329% | 30,363 |
| European (non-Finnish) | 0.00271% | 36,875 |

*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 **396** lies in the protein kinase domain; an α-helix.

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. p.Phe396= falls in the protein kinase domain.


### 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}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-05-07.

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2025–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-06-04 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-05-07 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2025-09-01 |

**Reported phenotype names (ClinVar):** not provided, not specified, AllHighlyPenetrant, none provided.

## 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.Ala134Thr](/variant/acvr1-p-ala134thr), [ACVR1 p.Arg147Gln](/variant/acvr1-p-arg147gln), [ACVR1 p.Arg160Ter](/variant/acvr1-p-arg160ter), [ACVR1 p.Arg307Gln](/variant/acvr1-p-arg307gln), [ACVR1 p.Arg417Gln](/variant/acvr1-p-arg417gln).

### 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 4280855). 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.*