Is FLNA p.Pro181= (c.543G>A) pathogenic?

FLNA p.Pro181= (c.543G>A) is classified Benign/Likely benign in FLNA (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-12-02). Ultra-rare (popmax 0.023%, mid); Associated with Melnick-Needles syndrome.

What condition is associated with FLNA p.Pro181= (c.543G>A)?

FLNA p.Pro181= (c.543G>A) is associated with Melnick-Needles syndrome, heterotopia, periventricular, X-linked dominant, otopalatodigital syndrome type 2 (ClinVar).

How common is FLNA p.Pro181= (c.543G>A) in the general population?

FLNA p.Pro181= (c.543G>A) is ultra-rare (popmax 0.023%, mid) (gnomAD).

FLNA p.Pro181=

c.543G>A · rs201486643 · VCV257473

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.023%, mid)

Conditions

Melnick-Needles syndrome

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	0.913	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.023% Middle Eastern · 1/4,354 alleles

Filtering AF 0.0165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0156%

Overall 0.0152% 184/1,209,444 alleles · ultra-rare exomes 168/1,097,645 · genomes 16/111,799 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.023%	4,354
European (non-Finnish)	0.0189%	5,296
Admixed American	0.00872%	11,462
Remaining individualsnot grpmax-eligible	0.0084%	11,901
South Asian	0.00704%	14,204
African / African-American	0.0035%	28,606

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.Pro181=
Coding: c.543G>A
MANE Select: NM_001110556
dbSNP: rs201486643
Type: single nucleotide variant
Location: chrX:154367921 (GRCh38)
Structure: AlphaFold pLDDT 77.37 · 26 PDB
Residue 181: a β-strand; the 'actin-binding' region; the calponin-homology (ch) 2 domain

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

Disease context

Melnick-Needles syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: heterotopia, periventricular, X-linked dominant otopalatodigital syndrome type 2 frontometaphyseal dysplasia familial thoracic aortic aneurysm and aortic dissection

Similar variants

FLNA p.Pro181Leu 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
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-pro181 (accessed [today's date]).

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