Is FLNA p.Pro740= (c.2220G>A) pathogenic?

FLNA p.Pro740= (c.2220G>A) is classified Benign/Likely benign in FLNA (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-11-28). Ultra-rare (popmax 0.0503%, eas); Associated with otopalatodigital syndrome type 2.

What condition is associated with FLNA p.Pro740= (c.2220G>A)?

FLNA p.Pro740= (c.2220G>A) is associated with otopalatodigital syndrome type 2, heterotopia, periventricular, X-linked dominant, Melnick-Needles syndrome (ClinVar).

How common is FLNA p.Pro740= (c.2220G>A) in the general population?

FLNA p.Pro740= (c.2220G>A) is ultra-rare (popmax 0.0503%, eas) (gnomAD).

FLNA p.Pro740=

c.2220G>A · rs202055800 · VCV390772

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0503%, eas)

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
Overall
CADD	0.113	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0503% East Asian · 17/33,775 alleles

Filtering AF 0.032% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0263%

Overall 0.00843% 102/1,209,549 alleles · ultra-rare exomes 95/1,097,192 · genomes 7/112,357 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0503%	1,987
Admixed American	0.0218%	4,588
Remaining individualsnot grpmax-eligible	0.0126%	7,932
South Asian	0.00879%	11,372
European (non-Finnish)	0.00693%	14,433
African / African-American	0.00349%	28,640

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.Pro740=
Coding: c.2220G>A
MANE Select: NM_001110556
dbSNP: rs202055800
Type: single nucleotide variant
Location: chrX:154364082 (GRCh38)
Structure: AlphaFold pLDDT 77.37 · 26 PDB
Residue 740: a β-strand

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.Pro740Leu 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
FLNA p.Ala1188Thr Pathogenic/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-pro740 (accessed [today's date]).

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