Is FLNA p.Pro817Ser (c.2449C>T) pathogenic?

FLNA p.Pro817Ser (c.2449C>T) is classified Conflicting classifications of pathogenicity in FLNA (ClinVar, Conflicting submitters, 17 submitters; last evaluated 2026-01-21). AlphaMissense: likely benign (0.1716); Ultra-rare (popmax 0.0931%, sas); Associated with connective tissue disorder.

What condition is associated with FLNA p.Pro817Ser (c.2449C>T)?

FLNA p.Pro817Ser (c.2449C>T) is associated with connective tissue disorder, disorder of sexual differentiation, heterotopia, periventricular, X-linked dominant (ClinVar).

How common is FLNA p.Pro817Ser (c.2449C>T) in the general population?

FLNA p.Pro817Ser (c.2449C>T) is ultra-rare (popmax 0.0931%, sas) (gnomAD).

What do computational predictors say about FLNA p.Pro817Ser (c.2449C>T)?

AlphaMissense predicts likely benign (score 0.1716) — an in-silico prediction, not a clinical call.

FLNA p.Pro817Ser

c.2449C>T · rs200053635 · VCV194727

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 17 submitters

AlphaMissense

likely benign

0.1716 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0931%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

connective tissue disorder

Computational evidence

Protein change
AlphaMissense	0.1716	likely benign
REVEL	0.32	indeterminate
SaProt	LLR -5.71	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 0.6, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 6,571 bp · p 2.7e-08 · regional, not allelic
Overall
CADD	22.0	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 0.0931% South Asian · 53/56,926 alleles

Filtering AF 0.073% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0659%

Overall 0.0446% 540/1,210,103 alleles · ultra-rare exomes 505/1,097,382 · genomes 35/112,721 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0931%	1,074
Middle Eastern	0.0915%	1,093
European (non-Finnish)	0.0506%	1,976
Remaining individualsnot grpmax-eligible	0.042%	2,380
Ashkenazi Jewishnot grpmax-eligible	0.0136%	7,346
Finnishnot grpmax-eligible	0.00868%	11,522
Admixed American	0.00435%	22,964
African / African-American	0.00174%	57,441

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.Pro817Ser
Coding: c.2449C>T
MANE Select: NM_001110556
dbSNP: rs200053635
Type: single nucleotide variant
Location: chrX:154362534 (GRCh38)
Structure: AlphaFold pLDDT 77.37 · 26 PDB

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

Disease context

connective tissue disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: disorder of sexual differentiation heterotopia, periventricular, X-linked dominant otopalatodigital syndrome type 2 Melnick-Needles syndrome frontometaphyseal dysplasia familial thoracic aortic aneurysm and aortic dissection Ehlers-Danlos syndrome

Similar variants

FLNA p.Pro817= 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-pro817ser (accessed [today's date]).

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