Is FLNA p.Ser612= (c.1836G>A) pathogenic?

FLNA p.Ser612= (c.1836G>A) is classified Conflicting classifications of pathogenicity in FLNA (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-08-18). Ultra-rare (popmax 0.0148%, eas); Associated with heterotopia, periventricular, X-linked dominant.

What condition is associated with FLNA p.Ser612= (c.1836G>A)?

FLNA p.Ser612= (c.1836G>A) is associated with heterotopia, periventricular, X-linked dominant, otopalatodigital syndrome type 2, Melnick-Needles syndrome (ClinVar).

How common is FLNA p.Ser612= (c.1836G>A) in the general population?

FLNA p.Ser612= (c.1836G>A) is ultra-rare (popmax 0.0148%, eas) (gnomAD).

FLNA p.Ser612=

c.1836G>A · rs1461515007 · VCV1188479

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0148%, eas)

Conditions

heterotopia, periventricular, X-linked dominant

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.48	acceptor gain · deltas
Pangolin	Δ0.20	gain · loss 0.06 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -20	GERP -3.7
Overall
CADD	15.06	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0148% East Asian · 5/33,721 alleles

Filtering AF 0.00581% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00374%

Overall 0.00273% 33/1,207,721 alleles · ultra-rare exomes 32/1,097,044 · genomes 1/110,677 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0148%	6,744
African / African-American	0.00352%	28,409
European (non-Finnish)	0.00279%	35,788
South Asian	0.00176%	56,669

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.Ser612=
Coding: c.1836G>A
MANE Select: NM_001110556
dbSNP: rs1461515007
Type: single nucleotide variant
Location: chrX:154364712 (GRCh38)
Structure: AlphaFold pLDDT 77.37 · 26 PDB
Residue 612: a β-strand

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

Disease context

heterotopia, periventricular, X-linked dominant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: otopalatodigital syndrome type 2 Melnick-Needles syndrome frontometaphyseal dysplasia

Similar variants

FLNA p.Ser612Leu 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-ser612 (accessed [today's date]).

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