Is FLNA p.Pro1531= (c.4593C>G) pathogenic?

FLNA p.Pro1531= (c.4593C>G) is classified Likely benign in FLNA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-15). Very rare (popmax 0.000447%, nfe); Associated with frontometaphyseal dysplasia.

What condition is associated with FLNA p.Pro1531= (c.4593C>G)?

FLNA p.Pro1531= (c.4593C>G) is associated with frontometaphyseal dysplasia, heterotopia, periventricular, X-linked dominant, otopalatodigital syndrome type 2 (ClinVar).

How common is FLNA p.Pro1531= (c.4593C>G) in the general population?

FLNA p.Pro1531= (c.4593C>G) is very rare (popmax 0.000447%, nfe) (gnomAD).

How is Frontometaphyseal dysplasia inherited?

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

FLNA p.Pro1531=

c.4593C>G · rs1370712483 · VCV1114819

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000447%, nfe)

Conditions

frontometaphyseal dysplasia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.1	GERP -3.7
Overall
CADD	5.926	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000447% European (non-Finnish) · 4/894,978 alleles

Filtering AF 0.000105% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.1e-05%

Overall 0.000331% 4/1,209,488 alleles · very rare exomes 1/1,097,729 · genomes 3/111,759 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: FLNA
Protein: p.Pro1531=
Coding: c.4593C>G
MANE Select: NM_001110556
dbSNP: rs1370712483
Type: single nucleotide variant
Location: chrX:154358450 (GRCh38)
Structure: AlphaFold pLDDT 77.37 · 26 PDB
Residue 1531: the 'interaction with furin' region

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.Pro1531Arg 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
FLNA c.987+1G>A Likely pathogenic ★★ same condition
FLNA p.Ala1188Thr Pathogenic/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-pro1531 (accessed [today's date]).

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