# NM_001110556.2(FLNA):c.20G>C (p.Arg7Pro)

https://sugi.bio/variant/flna-p-arg7pro

## Summary

**FLNA p.Arg7Pro (c.20G>C)** is classified **Conflicting classifications of pathogenicity** in FLNA (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-17). AlphaMissense: likely benign (0.1514); Very rare (popmax 0.0087%, afr); Associated with FLNA-related disorder.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs781814342 · 3 submitters · 5 linked conditions · AlphaMissense likely benign · very rare (popmax 0.0087%, afr)

## For patients & families {#patients}

This is a change in the FLNA gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to FLNA-related disorder.

*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 | [FLNA](https://sugi.bio/atlas/gene/FLNA/) |
| Protein change (HGVS p.) | p.Arg7Pro |
| Coding change (HGVS c.) | c.20G>C |
| MANE Select transcript | [NM_001110556](https://www.ncbi.nlm.nih.gov/nuccore/NM_001110556) |
| dbSNP | [rs781814342](https://www.ncbi.nlm.nih.gov/snp/rs781814342/) |
| Variant type | single nucleotide variant |
| Location | chrX:154371226-154371226 (GRCh38) |
| ClinVar | [VCV638389](https://www.ncbi.nlm.nih.gov/clinvar/variation/638389/) |

**All HGVS expressions:** `LRG_1340:g.8413G>C`, `LRG_1340t1:c.20G>C`, `LRG_745:g.1799C>G`, `NC_000023.10:g.153599594C>G`, `NC_000023.11:g.154371226C>G`, `NG_008677.1:g.1799C>G`, `NG_011506.2:g.8413G>C`, `NM_001110556.2:c.20G>C`, `NM_001456.4:c.20G>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1514)
- REVEL 0.468 (indeterminate)
- SaProt LLR -4.979 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate
- Conservation: phyloP -0.006, GERP 0.384 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 24.2**. 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 2.09** across the covering region of the MANE Select transcript (154,371,166–154,371,245), spanning 79 bp. Chi-square p 1e-08. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>T, Δ0.24 acceptor 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 **0.0087%** (afr) · FAF95 0.00337% · FAF99 0.00214% · 5/57,458 in the highest group · 18/1,200,008 alleles overall — very rare (popmax 0.0087%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0087% | 11,492 |
| European (non-Finnish) | 0.00146% | 68,551 |

*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}

**FLNA** population constraint: 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):

- **periventricular nodular heterotopia** — Definitive (XL)
- **familial thoracic aortic aneurysm and aortic dissection** — Limited (XL)

## Protein context {#protein}

Residue **7** lies in the 'disordered' region; the 'actin-binding' region.

AlphaFold model confidence (whole protein): pLDDT 77.37, 11% of residues very-high.

**26 experimental structure(s)** (PDB): [2AAV](https://www.rcsb.org/structure/2AAV), [2BP3](https://www.rcsb.org/structure/2BP3), [2BRQ](https://www.rcsb.org/structure/2BRQ), [2J3S](https://www.rcsb.org/structure/2J3S), [2JF1](https://www.rcsb.org/structure/2JF1), [2K3T](https://www.rcsb.org/structure/2K3T) — incl. mutant structure 3HOC.

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

*Describes the biological roles of FLNA (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:** FLNA's established molecular role includes G protein-coupled receptor binding. p.Arg7Pro falls in the disordered region.


### Pathways affected {#pathways}

FLNA participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Cell-extracellular matrix interactions](https://reactome.org/content/detail/R-HSA-446353) | curated |
| [GP1b-IX-V activation signalling](https://reactome.org/content/detail/R-HSA-430116) | curated |
| [OAS antiviral response](https://reactome.org/content/detail/R-HSA-8983711) | curated |
| [Platelet degranulation ](https://reactome.org/content/detail/R-HSA-114608) | curated |
| [RHO GTPases activate PAKs](https://reactome.org/content/detail/R-HSA-5627123) | curated |

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

**Molecular function:** G protein-coupled receptor binding, RNA binding, potassium channel regulator activity, kinase binding, small GTPase binding, Fc-gamma receptor I complex binding.

**Biological process:** adenylate cyclase-inhibiting dopamine receptor signaling pathway, negative regulation of transcription by RNA polymerase I, actin cytoskeleton organization, regulation of cell migration, protein localization to cell surface, negative regulation of protein catabolic process.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-11-17.

**Submitter consensus:** conflicting (2 Likely benign, 1 Uncertain significance).

**Submission history:** 3 submissions (2019–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genomic Research Center, Shahid Beheshti University of Medical Sciences | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-04-27 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2019-05-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-11-17 |

## Associated conditions {#conditions}

[FLNA-related disorder](https://sugi.bio/atlas/disease/flna-related-disorder/), [heterotopia, periventricular, X-linked dominant](https://sugi.bio/atlas/disease/heterotopia-periventricular-x-linked-dominant/), [otopalatodigital syndrome type 2](https://sugi.bio/atlas/disease/otopalatodigital-syndrome-type-2/), [Melnick-Needles syndrome](https://sugi.bio/atlas/disease/melnick-needles-syndrome/), [frontometaphyseal dysplasia](https://sugi.bio/atlas/disease/frontometaphyseal-dysplasia/).

**Reported phenotype names (ClinVar):** FLNA-related disorder, Frontometaphyseal dysplasia, Heterotopia, periventricular, X-linked dominant, Melnick-Needles syndrome, Oto-palato-digital syndrome, type II, not provided, none provided, PERIVENTRICULAR NODULAR HETEROTOPIA 4, HETEROTOPIA, PERIVENTRICULAR, 1, PERIVENTRICULAR NODULAR HETEROTOPIA 1.

## Same-residue context {#hotspot}

Residue **7** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [FLNA p.Arg7fs](/variant/flna-p-arg7fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related FLNA variant pages (same residue, condition, or type): [FLNA p.Arg7Trp](/variant/flna-p-arg7trp), [FLNA p.Arg7Gly](/variant/flna-p-arg7gly), [FLNA p.Arg7fs](/variant/flna-p-arg7fs), [FLNA p.Arg7=](/variant/flna-p-arg7), [FLNA c.1066-1G>A](/variant/flna-c-1066-minus-1g-a), [FLNA c.2022+1G>A](/variant/flna-c-2022-plus-1g-a), [FLNA c.4598+1G>A](/variant/flna-c-4598-plus-1g-a), [FLNA c.5417-2A>G](/variant/flna-c-5417-minus-2a-g).

### 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 638389). 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.*