Is FLNA p.Ala666= (c.1998G>A) pathogenic?

FLNA p.Ala666= (c.1998G>A) is classified Benign/Likely benign in FLNA (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-28). Low-frequency (popmax 1.16%, afr); Associated with otopalatodigital syndrome type 2.

What condition is associated with FLNA p.Ala666= (c.1998G>A)?

FLNA p.Ala666= (c.1998G>A) is associated with otopalatodigital syndrome type 2, heterotopia, periventricular, X-linked dominant, Melnick-Needles syndrome (ClinVar).

How common is FLNA p.Ala666= (c.1998G>A) in the general population?

FLNA p.Ala666= (c.1998G>A) is low-frequency (popmax 1.16%, afr) (gnomAD).

FLNA p.Ala666=

c.1998G>A · rs34510365 · VCV213439

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.16%, afr)

Conditions

otopalatodigital syndrome type 2

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	0.045	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.16% African / African-American · 662/57,016 alleles

Filtering AF 1.09% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.06%

Overall 0.06% 725/1,208,097 alleles · low-frequency exomes 398/1,096,959 · genomes 327/111,138 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.16%	86
Remaining individualsnot grpmax-eligible	0.0819%	1,221
Middle Eastern	0.023%	4,350
Admixed American	0.0219%	4,570
South Asian	0.00529%	18,921
European (non-Finnish)	0.00112%	89,494

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.Ala666=
Coding: c.1998G>A
MANE Select: NM_001110556
dbSNP: rs34510365
Type: single nucleotide variant
Location: chrX:154364550 (GRCh38)
Structure: AlphaFold pLDDT 77.37 · 26 PDB
Residue 666: an α-helix

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

Disease context

otopalatodigital syndrome type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: heterotopia, periventricular, X-linked dominant Melnick-Needles syndrome frontometaphyseal dysplasia familial thoracic aortic aneurysm and aortic dissection

Similar variants

FLNA p.Ala666Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
FLNA p.Ala666Val Conflicting classifications of pathogenicity ★ ⚠ 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-ala666 (accessed [today's date]).

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