Is FLNA p.Phe49= (c.147C>T) pathogenic?

FLNA p.Phe49= (c.147C>T) is classified Likely benign in FLNA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-20). Very rare (popmax 0.00663%, amr); Associated with Melnick-Needles syndrome.

What condition is associated with FLNA p.Phe49= (c.147C>T)?

FLNA p.Phe49= (c.147C>T) is associated with Melnick-Needles syndrome, heterotopia, periventricular, X-linked dominant, otopalatodigital syndrome type 2 (ClinVar).

How common is FLNA p.Phe49= (c.147C>T) in the general population?

FLNA p.Phe49= (c.147C>T) is very rare (popmax 0.00663%, amr) (gnomAD).

FLNA p.Phe49=

c.147C>T · VCV3758398

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00663%, amr)

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 3.5	GERP -0.43, phastCons 1
Overall
CADD	13.34	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00663% Admixed American · 3/45,245 alleles

Filtering AF 0.00176% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000887%

Overall 0.000275% 3/1,090,493 alleles · very rare

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.Phe49=
Coding: c.147C>T
MANE Select: NM_001110556
Type: single nucleotide variant
Location: chrX:154371099 (GRCh38)
Structure: AlphaFold pLDDT 77.37 · 26 PDB
Residue 49: an α-helix; the calponin-homology (ch) 1 domain; the 'actin-binding' region

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

Similar variants

FLNA p.Phe49fs Pathogenic ★ same residue
FLNA p.Phe49Leu 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-phe49 (accessed [today's date]).

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