Is FLNA p.His147= (c.441C>T) pathogenic?

FLNA p.His147= (c.441C>T) is classified Likely benign in FLNA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-06). Ultra-rare (popmax 0.0415%, amr); Associated with otopalatodigital syndrome type 2.

What condition is associated with FLNA p.His147= (c.441C>T)?

FLNA p.His147= (c.441C>T) is associated with otopalatodigital syndrome type 2, heterotopia, periventricular, X-linked dominant, Melnick-Needles syndrome (ClinVar).

How common is FLNA p.His147= (c.441C>T) in the general population?

FLNA p.His147= (c.441C>T) is ultra-rare (popmax 0.0415%, amr) (gnomAD).

FLNA p.His147=

c.441C>T · rs781951563 · VCV712273

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0415%, amr)

Conditions

otopalatodigital syndrome type 2

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>C here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.7	GERP 1.8, phastCons 1
Overall
CADD	12.89	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0415% Admixed American · 19/45,772 alleles

Filtering AF 0.0271% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0226%

Overall 0.00166% 20/1,204,794 alleles · ultra-rare exomes 18/1,093,243 · genomes 2/111,551 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0415%	2,409
European (non-Finnish)	0.000112%	890,734

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.His147=
Coding: c.441C>T
MANE Select: NM_001110556
dbSNP: rs781951563
Type: single nucleotide variant
Location: chrX:154368023 (GRCh38)
Structure: AlphaFold pLDDT 77.37 · 26 PDB
Residue 147: 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

otopalatodigital syndrome type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: heterotopia, periventricular, X-linked dominant Melnick-Needles syndrome frontometaphyseal dysplasia familial thoracic aortic aneurysm and aortic dissection

Similar variants

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
FLNA p.Arg1515Ter 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-his147 (accessed [today's date]).

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