Is FLNA p.Ser2180= (c.6540C>T) pathogenic?

FLNA p.Ser2180= (c.6540C>T) is classified Likely benign in FLNA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-03). Ultra-rare (popmax 0.0118%, eas); Associated with heterotopia, periventricular, X-linked dominant.

What condition is associated with FLNA p.Ser2180= (c.6540C>T)?

FLNA p.Ser2180= (c.6540C>T) is associated with heterotopia, periventricular, X-linked dominant, otopalatodigital syndrome type 2, Melnick-Needles syndrome (ClinVar).

How common is FLNA p.Ser2180= (c.6540C>T) in the general population?

FLNA p.Ser2180= (c.6540C>T) is ultra-rare (popmax 0.0118%, eas) (gnomAD).

FLNA p.Ser2180=

c.6540C>T · rs781992483 · VCV413407

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0118%, eas)

Conditions

heterotopia, periventricular, X-linked dominant

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 1.3	GERP 0.75, phastCons 1
Overall
CADD	7.252	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0118% East Asian · 4/33,858 alleles

Filtering AF 0.00395% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00235%

Overall 0.000413% 5/1,212,094 alleles · ultra-rare exomes 5/1,097,807 · genomes 0/114,287 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0118%	8,465
European (non-Finnish)	0.000112%	895,600

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.Ser2180=
Coding: c.6540C>T
MANE Select: NM_001110556
dbSNP: rs781992483
Type: single nucleotide variant
Location: chrX:154352410 (GRCh38)
Structure: AlphaFold pLDDT 77.37 · 26 PDB
Residue 2180: a modified residue (phosphoserine)

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

Disease context

heterotopia, periventricular, X-linked dominant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: otopalatodigital syndrome type 2 Melnick-Needles syndrome frontometaphyseal dysplasia

Similar variants

FLNA p.Ser2180Asn Uncertain significance ★ ⚠ same residue
FLNA p.Ser2180Arg Likely benign ★ 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-ser2180 (accessed [today's date]).

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