# NM_001110556.2(FLNA):c.1848A>G (p.Pro616=)

https://sugi.bio/variant/flna-p-pro616

## Summary

**FLNA p.Pro616= (c.1848A>G)** is classified **Likely benign** in FLNA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-08-14). Very rare (popmax 0.00297%, eas); Associated with heterotopia, periventricular, X-linked dominant.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs782353479 · 3 submitters · 5 linked conditions · very rare (popmax 0.00297%, eas)

## For patients & families {#patients}

This is a change in the FLNA gene that is classified as likely benign — not considered disease-causing, 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.Pro616= |
| Coding change (HGVS c.) | c.1848A>G |
| MANE Select transcript | [NM_001110556](https://www.ncbi.nlm.nih.gov/nuccore/NM_001110556) |
| dbSNP | [rs782353479](https://www.ncbi.nlm.nih.gov/snp/rs782353479/) |
| Variant type | single nucleotide variant |
| Location | chrX:154364700-154364700 (GRCh38) |
| ClinVar | [VCV1781270](https://www.ncbi.nlm.nih.gov/clinvar/variation/1781270/) |

**All HGVS expressions:** `LRG_1340:g.14939A>G`, `LRG_1340t1:c.1848A>G`, `NC_000023.10:g.153593068T>C`, `NC_000023.11:g.154364700T>C`, `NG_011506.2:g.14939A>G`, `NM_001110556.2:c.1848A>G`, `NM_001456.4:c.1848A>G`

## 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 -20, GERP -3.66 — fast-evolving / accelerated position
- CADD: **PHRED 0.684**. 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: **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, T>A, IS in the release and scores Δ0.21 acceptor gain, 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.*
- Population frequency (gnomAD v4.1): grpmax **0.00297%** (eas) · 1/33,704 in the highest group · 6/1,207,965 alleles overall — very rare (popmax 0.00297%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0084% | 11,900 |
| East Asian (grpmax) | 0.00297% | 33,704 |
| South Asian | 0.00176% | 56,679 |

Remaining individuals 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 **616** 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}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-08-14.

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

**Submission history:** 3 submissions (2020–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2020-09-29 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-08-14 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-07-15 |

## 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/), [familial thoracic aortic aneurysm and aortic dissection](https://sugi.bio/atlas/disease/familial-thoracic-aortic-aneurysm-and-aortic-dissection/).

**Reported phenotype names (ClinVar):** Heterotopia, periventricular, X-linked dominant, Familial thoracic aortic aneurysm and aortic dissection, Frontometaphyseal dysplasia, Melnick-Needles syndrome, Oto-palato-digital syndrome, type II, not specified, AllHighlyPenetrant, 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 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), [FLNA p.Arg1515Ter](/variant/flna-p-arg1515ter).

### 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 1781270). 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.*