# NM_001110556.2(FLNA):c.289C>T (p.Pro97Ser)

https://sugi.bio/variant/flna-p-pro97ser

## Summary

**FLNA p.Pro97Ser (c.289C>T)** is classified **Uncertain significance** in FLNA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-17). AlphaMissense: likely pathogenic (0.9976); Absent from gnomAD v4.1; Associated with cardiac valvular dysplasia, X-linked.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 9 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the FLNA gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to cardiac valvular dysplasia, X-linked.

*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/0001096/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.Pro97Ser |
| Coding change (HGVS c.) | c.289C>T |
| MANE Select transcript | [NM_001110556](https://www.ncbi.nlm.nih.gov/nuccore/NM_001110556) |
| Variant type | single nucleotide variant |
| Location | chrX:154370957-154370957 (GRCh38) |
| ClinVar | [VCV3367185](https://www.ncbi.nlm.nih.gov/clinvar/variation/3367185/) |

**All HGVS expressions:** `LRG_1340:g.8682C>T`, `LRG_1340t1:c.289C>T`, `LRG_745:g.1530G>A`, `NC_000023.10:g.153599325G>A`, `NC_000023.11:g.154370957G>A`, `NG_008677.1:g.1530G>A`, `NG_011506.2:g.8682C>T`, `NG_147834.1:g.43G>A`, `NM_001110556.2:c.289C>T`, `NM_001456.4:c.289C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9976)
- REVEL 0.843 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -7.631 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL call this damaging; SaProt does not
- Conservation: phyloP 8.124, GERP 0.491, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 4%** most-pathogenic-predicted substitutions in FLNA (of 15,638 modeled).
- CADD: **PHRED 26.6**. 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 0.30** across the covering region of the MANE Select transcript (154,366,821–154,371,165), spanning 4,344 bp — the region is depleted of missense variation. Chi-square p 1.3e-27. 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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, triplosensitivity 0 (0–3 scale). *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 **97** lies in the calponin-homology (ch) 1 domain; 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.Pro97Ser falls in the calponin-homology (ch) 1 domain.


### 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-10-17.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-10-17 |

## Associated conditions {#conditions}

[cardiac valvular dysplasia, X-linked](https://sugi.bio/atlas/disease/cardiac-valvular-dysplasia-x-linked/), [intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked](https://sugi.bio/atlas/disease/intestinal-pseudoobstruction-neuronal-chronic-idiopathic-x-linked/), [heterotopia, periventricular, X-linked dominant](https://sugi.bio/atlas/disease/heterotopia-periventricular-x-linked-dominant/), [terminal osseous dysplasia-pigmentary defects syndrome](https://sugi.bio/atlas/disease/terminal-osseous-dysplasia-pigmentary-defects-syndrome/), [FG syndrome 2](https://sugi.bio/atlas/disease/fg-syndrome-2/), [otopalatodigital syndrome type 2](https://sugi.bio/atlas/disease/otopalatodigital-syndrome-type-2/), [Melnick-Needles syndrome](https://sugi.bio/atlas/disease/melnick-needles-syndrome/), [otopalatodigital syndrome type 1](https://sugi.bio/atlas/disease/otopalatodigital-syndrome-type-1/), [frontometaphyseal dysplasia 1](https://sugi.bio/atlas/disease/frontometaphyseal-dysplasia-1/).

**Reported phenotype names (ClinVar):** Cardiac valvular dysplasia, X-linked, FG syndrome 2, Frontometaphyseal dysplasia 1, Heterotopia, periventricular, X-linked dominant, Intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked, Melnick-Needles syndrome, Oto-palato-digital syndrome, type I, Oto-palato-digital syndrome, type II, Terminal osseous dysplasia-pigmentary defects syndrome, FLNA-Related X-linked Cardiac Valvular Dysplasia.

## Similar variants {#similar}

Related FLNA variant pages (same residue, condition, or type): [FLNA p.Pro97Thr](/variant/flna-p-pro97thr), [FLNA p.Pro97=](/variant/flna-p-pro97), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 3367185). 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.*