Is FLNA p.Ala818= (c.2454C>T) pathogenic?

FLNA p.Ala818= (c.2454C>T) is classified Likely benign in FLNA (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-12-15). Ultra-rare (popmax 0.0331%, afr); Associated with heterotopia, periventricular, X-linked dominant.

What condition is associated with FLNA p.Ala818= (c.2454C>T)?

FLNA p.Ala818= (c.2454C>T) is associated with heterotopia, periventricular, X-linked dominant, otopalatodigital syndrome type 2, Melnick-Needles syndrome (ClinVar).

How common is FLNA p.Ala818= (c.2454C>T) in the general population?

FLNA p.Ala818= (c.2454C>T) is ultra-rare (popmax 0.0331%, afr) (gnomAD).

FLNA p.Ala818=

c.2454C>T · rs374672498 · VCV390773

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0331%, afr)

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 -3.4
Overall
CADD	0.042	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0331% African / African-American · 19/57,456 alleles

Filtering AF 0.0216% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.018%

Overall 0.00339% 41/1,210,066 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0331%	3,024
Middle Eastern	0.0229%	4,366
South Asian	0.00527%	18,976
Admixed American	0.00435%	22,967
Finnishnot grpmax-eligible	0.00217%	46,063
Remaining individualsnot grpmax-eligible	0.0021%	47,600
European (non-Finnish)	0.00156%	63,943

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.Ala818=
Coding: c.2454C>T
MANE Select: NM_001110556
dbSNP: rs374672498
Type: single nucleotide variant
Location: chrX:154362529 (GRCh38)
Structure: AlphaFold pLDDT 77.37 · 26 PDB

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 familial thoracic aortic aneurysm and aortic dissection

Similar variants

FLNA p.Ala818Thr Benign/Likely benign ★★ same residue
FLNA p.Ala818fs Pathogenic ★ 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-ala818 (accessed [today's date]).

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