Is FLNA p.Lys43= (c.129G>A) pathogenic?

FLNA p.Lys43= (c.129G>A) is classified Likely benign in FLNA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-05-07). Very rare (popmax 0.00179%, sas); Associated with Melnick-Needles syndrome.

What condition is associated with FLNA p.Lys43= (c.129G>A)?

FLNA p.Lys43= (c.129G>A) is associated with Melnick-Needles syndrome, connective tissue disorder, heterotopia, periventricular, X-linked dominant (ClinVar).

How common is FLNA p.Lys43= (c.129G>A) in the general population?

FLNA p.Lys43= (c.129G>A) is very rare (popmax 0.00179%, sas) (gnomAD).

FLNA p.Lys43=

c.129G>A · rs1569551929 · VCV561302

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00179%, sas)

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 -0.18	GERP -0.65, phastCons 0.4
Overall
CADD	13.6	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00179% South Asian · 1/55,822 alleles

Filtering AF 3.7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.000249% 3/1,203,813 alleles · very rare exomes 3/1,090,046 · genomes 0/113,767 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00179%	55,822
European (non-Finnish)	0.000224%	445,953

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.Lys43=
Coding: c.129G>A
MANE Select: NM_001110556
dbSNP: rs1569551929
Type: single nucleotide variant
Location: chrX:154371117 (GRCh38)
Structure: AlphaFold pLDDT 77.37 · 26 PDB
Residue 43: an α-helix; the calponin-homology (ch) 1 domain; the 'actin-binding' region; a cross-link site

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

Similar variants

FLNA p.Lys43Asn 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-lys43 (accessed [today's date]).

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