Is FLNA p.Pro348= (c.1044C>T) pathogenic?

FLNA p.Pro348= (c.1044C>T) is classified Benign/Likely benign in FLNA (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-02). Rare (popmax 0.106%, afr); Associated with otopalatodigital syndrome type 2.

What condition is associated with FLNA p.Pro348= (c.1044C>T)?

FLNA p.Pro348= (c.1044C>T) is associated with otopalatodigital syndrome type 2, heterotopia, periventricular, X-linked dominant, Melnick-Needles syndrome (ClinVar).

How common is FLNA p.Pro348= (c.1044C>T) in the general population?

FLNA p.Pro348= (c.1044C>T) is rare (popmax 0.106%, afr) (gnomAD).

FLNA p.Pro348=

c.1044C>T · rs375821223 · VCV213459

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

rare (popmax 0.106%, afr)

Conditions

otopalatodigital syndrome type 2

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	GERP -3.7
Overall
CADD	5.248	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.106% African / African-American · 61/57,486 alleles

Filtering AF 0.0848% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.077%

Overall 0.0192% 233/1,210,570 alleles · rare exomes 200/1,097,706 · genomes 33/112,864 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.106%	942
Middle Eastern	0.0457%	2,187
Remaining individualsnot grpmax-eligible	0.0189%	5,289
European (non-Finnish)	0.0168%	5,966
Admixed American	0.0109%	9,200
Finnishnot grpmax-eligible	0.00856%	11,678
East Asian	0.00296%	33,798
South Asian	0.00176%	56,912

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.Pro348=
Coding: c.1044C>T
MANE Select: NM_001110556
dbSNP: rs375821223
Type: single nucleotide variant
Location: chrX:154366583 (GRCh38)
Structure: AlphaFold pLDDT 77.37 · 26 PDB

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 p.Pro348Ala Conflicting classifications of pathogenicity ★ ⚠ 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-pro348 (accessed [today's date]).

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