Is FLNA p.Ser1256= (c.3768C>T) pathogenic?

FLNA p.Ser1256= (c.3768C>T) is classified Likely benign in FLNA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-16). Very rare (popmax 0.00592%, eas); Associated with Melnick-Needles syndrome.

What condition is associated with FLNA p.Ser1256= (c.3768C>T)?

FLNA p.Ser1256= (c.3768C>T) is associated with Melnick-Needles syndrome, heterotopia, periventricular, X-linked dominant, otopalatodigital syndrome type 2 (ClinVar).

How common is FLNA p.Ser1256= (c.3768C>T) in the general population?

FLNA p.Ser1256= (c.3768C>T) is very rare (popmax 0.00592%, eas) (gnomAD).

FLNA p.Ser1256=

c.3768C>T · rs782528841 · VCV533600

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00592%, eas)

Conditions

Melnick-Needles syndrome

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 · G>T here scores Δ0.40 · evaluated, not missing
Constraint at this position
Conservation	phyloP -20	GERP -3
Overall
CADD	0.204	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00592% East Asian · 2/33,764 alleles

Filtering AF 0.000981% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000367%

Overall 0.000662% 8/1,208,556 alleles · very rare exomes 7/1,095,770 · genomes 1/112,786 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00592%	16,882
Admixed American	0.00217%	46,016
Remaining individualsnot grpmax-eligible	0.0021%	47,552
European (non-Finnish)	0.000447%	223,487

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.Ser1256=
Coding: c.3768C>T
MANE Select: NM_001110556
dbSNP: rs782528841
Type: single nucleotide variant
Location: chrX:154360027 (GRCh38)
Structure: AlphaFold pLDDT 77.37 · 26 PDB

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 frontometaphyseal dysplasia 1

Similar variants

FLNA p.Ser1256Pro Uncertain significance ★★ ⚠ same residue
FLNA p.Ser1256Tyr 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-ser1256 (accessed [today's date]).

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