Is FLNA p.Pro480= (c.1440G>A) pathogenic?

FLNA p.Pro480= (c.1440G>A) is classified Likely benign in FLNA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-03). Ultra-rare (popmax 0.0351%, sas); Associated with heterotopia, periventricular, X-linked dominant.

What condition is associated with FLNA p.Pro480= (c.1440G>A)?

FLNA p.Pro480= (c.1440G>A) is associated with heterotopia, periventricular, X-linked dominant, otopalatodigital syndrome type 2, Melnick-Needles syndrome (ClinVar).

How common is FLNA p.Pro480= (c.1440G>A) in the general population?

FLNA p.Pro480= (c.1440G>A) is ultra-rare (popmax 0.0351%, sas) (gnomAD).

FLNA p.Pro480=

c.1440G>A · rs781919163 · VCV1639299

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0351%, sas)

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 -20	GERP -3.7
Overall
CADD	0.472	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0351% South Asian · 20/56,909 alleles

Filtering AF 0.0233% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0195%

Overall 0.00215% 26/1,210,045 alleles · ultra-rare exomes 23/1,096,890 · genomes 3/113,155 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0351%	2,845
East Asian	0.00592%	16,888
African / African-American	0.00347%	28,802
Remaining individualsnot grpmax-eligible	0.0021%	47,569
European (non-Finnish)	0.000112%	895,151

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.Pro480=
Coding: c.1440G>A
MANE Select: NM_001110556
dbSNP: rs781919163
Type: single nucleotide variant
Location: chrX:154365476 (GRCh38)
Structure: AlphaFold pLDDT 77.37 · 26 PDB
Residue 480: an α-helix

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.Pro480Gln Uncertain significance ★ ⚠ same residue
FLNA p.Pro480Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
FLNA p.Pro480Ser Uncertain significance ★ ⚠ same residue
FLNA p.Pro480Thr 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

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-pro480 (accessed [today's date]).

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