Is FLNA p.Pro207Ser (c.619C>T) pathogenic?

FLNA p.Pro207Ser (c.619C>T) is classified Uncertain significance in FLNA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-29). AlphaMissense: likely pathogenic (0.9467); Absent from gnomAD v4.1; Associated with frontometaphyseal dysplasia.

What condition is associated with FLNA p.Pro207Ser (c.619C>T)?

FLNA p.Pro207Ser (c.619C>T) is associated with frontometaphyseal dysplasia, heterotopia, periventricular, X-linked dominant, otopalatodigital syndrome type 2 (ClinVar).

How common is FLNA p.Pro207Ser (c.619C>T) in the general population?

FLNA p.Pro207Ser (c.619C>T) is absent from gnomAD v4.1 (gnomAD).

How is Frontometaphyseal dysplasia inherited?

Typically Autosomal dominant, X-linked dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about FLNA p.Pro207Ser (c.619C>T)?

AlphaMissense predicts likely pathogenic (score 0.9467) — an in-silico prediction, not a clinical call.

FLNA p.Pro207Ser

c.619C>T · rs1603363256 · VCV652826

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9467 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

frontometaphyseal dysplasia

Computational evidence

Protein change
AlphaMissense	0.9467	likely pathogenic
REVEL	0.912	moderately pathogenic-leaning
SaProt	LLR -10.70	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.30	constrained · MANE · 4,344 bp · p 1.3e-27 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FLNA
Protein: p.Pro207Ser
Coding: c.619C>T
MANE Select: NM_001110556
dbSNP: rs1603363256
Type: single nucleotide variant
Location: chrX:154367845 (GRCh38)
Structure: AlphaFold pLDDT 77.37 · 26 PDB
Residue 207: a UniProt-annotated variant site (in opd1); the 'actin-binding' region; the calponin-homology (ch) 2 domain

Full FLNA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

frontometaphyseal dysplasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: heterotopia, periventricular, X-linked dominant otopalatodigital syndrome type 2 Melnick-Needles syndrome

For Frontometaphyseal dysplasia (Orphanet):

Inheritance: Autosomal dominant, X-linked dominant
Onset: Neonatal

Similar variants

FLNA p.Pro207Leu Pathogenic/Likely pathogenic ★★ same residue
FLNA p.Pro207= Conflicting classifications of pathogenicity ★ same residue
FLNA p.Pro207Gln Uncertain significance ★ ⚠ same residue
FLNA c.1066-1G>A Pathogenic/Likely pathogenic ★★ same condition
FLNA c.2022+1G>A Pathogenic ★★ same condition
FLNA c.4598+1G>A Pathogenic/Likely pathogenic ★★ same condition
FLNA c.5417-2A>G Likely pathogenic ★★ same condition
FLNA c.868+1G>A Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/flna-p-pro207ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown