Is FLNA p.Pro348Ala (c.1042C>G) pathogenic?

FLNA p.Pro348Ala (c.1042C>G) is classified Conflicting classifications of pathogenicity in FLNA (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-10-17). AlphaMissense: likely pathogenic (0.8467); Ultra-rare (popmax 0.0326%, eas); Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with FLNA p.Pro348Ala (c.1042C>G)?

FLNA p.Pro348Ala (c.1042C>G) is associated with familial thoracic aortic aneurysm and aortic dissection, heterotopia, periventricular, X-linked dominant, otopalatodigital syndrome type 2 (ClinVar).

How common is FLNA p.Pro348Ala (c.1042C>G) in the general population?

FLNA p.Pro348Ala (c.1042C>G) is ultra-rare (popmax 0.0326%, eas) (gnomAD).

What do computational predictors say about FLNA p.Pro348Ala (c.1042C>G)?

AlphaMissense predicts likely pathogenic (score 0.8467) — an in-silico prediction, not a clinical call.

FLNA p.Pro348Ala

Q: How is Familial thoracic aortic aneurysm and aortic dissection inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.1042C>G · rs782643025 · VCV264416

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8467 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0326%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.8467	likely pathogenic
REVEL	0.868	moderately pathogenic-leaning
SaProt	LLR -14.02	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.20	donor loss · deltas
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 6,571 bp · p 2.7e-08 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0326% East Asian · 11/33,794 alleles

Filtering AF 0.0182% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0141%

Overall 0.000991% 12/1,210,621 alleles · ultra-rare exomes 11/1,097,693 · genomes 1/112,928 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0326%	3,072
Remaining individualsnot grpmax-eligible	0.0021%	47,619

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.Pro348Ala
Coding: c.1042C>G
MANE Select: NM_001110556
dbSNP: rs782643025
Type: single nucleotide variant
Location: chrX:154366585 (GRCh38)
Structure: AlphaFold pLDDT 77.37 · 26 PDB

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

Disease context

familial thoracic aortic aneurysm and aortic dissection — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: heterotopia, periventricular, X-linked dominant otopalatodigital syndrome type 2 Melnick-Needles syndrome frontometaphyseal dysplasia

For Familial thoracic aortic aneurysm and aortic dissection (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

FLNA p.Pro348= Benign/Likely benign ★★ 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-pro348ala (accessed [today's date]).

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