Is FLNA p.Val2592= (c.7776G>C) pathogenic?

FLNA p.Val2592= (c.7776G>C) is classified Likely benign in FLNA (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-01). Very rare (popmax 0.00873%, amr); Associated with otopalatodigital syndrome type 2.

What condition is associated with FLNA p.Val2592= (c.7776G>C)?

FLNA p.Val2592= (c.7776G>C) is associated with otopalatodigital syndrome type 2, heterotopia, periventricular, X-linked dominant, Melnick-Needles syndrome (ClinVar).

How common is FLNA p.Val2592= (c.7776G>C) in the general population?

FLNA p.Val2592= (c.7776G>C) is very rare (popmax 0.00873%, amr) (gnomAD).

FLNA p.Val2592=

c.7776G>C · rs369380495 · VCV386095

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00873%, amr)

Conditions

otopalatodigital syndrome type 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP -3.2	GERP -2.4
Overall
CADD	2.104	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00873% Admixed American · 4/45,831 alleles

Filtering AF 0.00293% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00177%

Overall 0.000496% 6/1,208,708 alleles · very rare exomes 2/1,096,224 · genomes 4/112,484 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00873%	11,458
Remaining individualsnot grpmax-eligible	0.00421%	23,764

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.Val2592=
Coding: c.7776G>C
MANE Select: NM_001110556
dbSNP: rs369380495
Type: single nucleotide variant
Location: chrX:154349017 (GRCh38)
Structure: AlphaFold pLDDT 77.37 · 26 PDB
Residue 2592: a β-strand; the 'self-association site, tail' region

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.Val2592Leu Uncertain significance ★ ⚠ same residue
FLNA p.Val2592Gly 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
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-val2592 (accessed [today's date]).

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