# NM_001110556.2(FLNA):c.6415C>T (p.Arg2139Trp)

https://sugi.bio/variant/flna-p-arg2139trp

## Summary

**FLNA p.Arg2139Trp (c.6415C>T)** is classified **Conflicting classifications of pathogenicity** in FLNA (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-07-14). AlphaMissense: ambiguous (0.5227); Very rare (popmax 0.00296%, eas); Associated with heterotopia, periventricular, X-linked dominant.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs782761341 · 3 submitters · 4 linked conditions · AlphaMissense ambiguous · very rare (popmax 0.00296%, eas)

## 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 heterotopia, periventricular, X-linked dominant.

*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/0007371/index) · [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.Arg2139Trp |
| Coding change (HGVS c.) | c.6415C>T |
| MANE Select transcript | [NM_001110556](https://www.ncbi.nlm.nih.gov/nuccore/NM_001110556) |
| dbSNP | [rs782761341](https://www.ncbi.nlm.nih.gov/snp/rs782761341/) |
| Variant type | single nucleotide variant |
| Location | chrX:154352640-154352640 (GRCh38) |
| ClinVar | [VCV465012](https://www.ncbi.nlm.nih.gov/clinvar/variation/465012/) |

**All HGVS expressions:** `LRG_1340:g.26999C>T`, `LRG_1340t1:c.6415C>T`, `NC_000023.10:g.153581008G>A`, `NC_000023.11:g.154352640G>A`, `NG_011506.2:g.26999C>T`, `NM_001110556.2:c.6415C>T`, `NM_001456.4:c.6391C>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this damaging; AlphaMissense is indeterminate — descriptive only.

- AlphaMissense **ambiguous** (0.5227) — no call either way
- REVEL 0.7 (pathogenic-leaning)
- SaProt LLR -11.978 (damaging)
- → **In-silico consensus:** REVEL and SaProt both call this damaging; AlphaMissense is indeterminate
- Conservation: phyloP 5.123, GERP -2.1, phastCons 1 — highly conserved
- CADD: **PHRED 23.9**. 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 0.74** across the covering region of the MANE Select transcript (154,348,852–154,360,184), spanning 11,332 bp. Chi-square p 3.1e-20. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. This allele is not in the release, so all four of its deltas are under 0.2. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, and here that is proven rather than inferred: a different substitution at this very position, G>T, IS in the release and scores Δ0.23 acceptor loss, so SpliceAI evaluated this position and this allele was not among the ones that cleared the filter. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Pangolin: Δ**0.25** (loss), gain 0.01 / loss 0.25. SpliceAI below 0.2. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00296%** (eas) · 1/33,807 in the highest group · 5/1,210,572 alleles overall — very rare (popmax 0.00296%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.00433% | 23,074 |
| East Asian (grpmax) | 0.00296% | 33,807 |
| South Asian | 0.00176% | 56,977 |
| European (non-Finnish) | 0.000112% | 895,351 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **2139** lies in a β-strand.

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.


### 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 2025-07-14.

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

**Submission history:** 3 submissions (2023–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-07-14 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-08-24 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-03-28 |

## Associated conditions {#conditions}

[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):** Heterotopia, periventricular, X-linked dominant, Frontometaphyseal dysplasia, Melnick-Needles syndrome, Oto-palato-digital syndrome, type II, not specified, not provided, none provided, PERIVENTRICULAR NODULAR HETEROTOPIA 1, X-linked periventricular heterotopia, PERIVENTRICULAR NODULAR HETEROTOPIA 4.

## Similar variants {#similar}

Related FLNA variant pages (same residue, condition, or type): [FLNA p.Arg2139Gln](/variant/flna-p-arg2139gln), [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), [FLNA c.868+1G>A](/variant/flna-c-868-plus-1g-a), [FLNA c.987+1G>A](/variant/flna-c-987-plus-1g-a), [FLNA p.Ala1188Thr](/variant/flna-p-ala1188thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 465012). 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.*