Is FLNA p.Ser72= (c.216C>T) pathogenic?

FLNA p.Ser72= (c.216C>T) is classified Likely benign in FLNA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-03-08). Ultra-rare (popmax 0.023%, mid); Associated with frontometaphyseal dysplasia.

What condition is associated with FLNA p.Ser72= (c.216C>T)?

FLNA p.Ser72= (c.216C>T) is associated with frontometaphyseal dysplasia, heterotopia, periventricular, X-linked dominant, otopalatodigital syndrome type 2 (ClinVar).

How common is FLNA p.Ser72= (c.216C>T) in the general population?

FLNA p.Ser72= (c.216C>T) is ultra-rare (popmax 0.023%, mid) (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.Ser72=

c.216C>T · rs1557180194 · VCV1093144

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.023%, mid)

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 0.5	GERP -1.9, phastCons 0.98
Overall
CADD	13.06	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.023% Middle Eastern · 1/4,340 alleles

Filtering AF 3.7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.000249% 3/1,206,636 alleles · ultra-rare exomes 2/1,093,344 · genomes 1/113,292 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.023%	4,340
European (non-Finnish)	0.000224%	446,578

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.Ser72=
Coding: c.216C>T
MANE Select: NM_001110556
dbSNP: rs1557180194
Type: single nucleotide variant
Location: chrX:154371030 (GRCh38)
Structure: AlphaFold pLDDT 77.37 · 26 PDB
Residue 72: a turn; the calponin-homology (ch) 1 domain; the 'actin-binding' 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.Ser72Ile Uncertain significance ★ ⚠ same residue
FLNA p.Ser72Arg 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

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-ser72 (accessed [today's date]).

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