Is FLNA p.Pro565Ser (c.1693C>T) pathogenic?

FLNA p.Pro565Ser (c.1693C>T) is classified Conflicting classifications of pathogenicity in FLNA (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-09). AlphaMissense: likely pathogenic (0.8335); Ultra-rare (popmax 0.0503%, eas); Associated with heterotopia, periventricular, X-linked dominant.

What condition is associated with FLNA p.Pro565Ser (c.1693C>T)?

FLNA p.Pro565Ser (c.1693C>T) is associated with heterotopia, periventricular, X-linked dominant, otopalatodigital syndrome type 2, Melnick-Needles syndrome (ClinVar).

How common is FLNA p.Pro565Ser (c.1693C>T) in the general population?

FLNA p.Pro565Ser (c.1693C>T) is ultra-rare (popmax 0.0503%, eas) (gnomAD).

What do computational predictors say about FLNA p.Pro565Ser (c.1693C>T)?

AlphaMissense predicts likely pathogenic (score 0.8335) — an in-silico prediction, not a clinical call.

FLNA p.Pro565Ser

c.1693C>T · rs782580317 · VCV569957

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8335 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0503%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

heterotopia, periventricular, X-linked dominant

Computational evidence

Protein change
AlphaMissense	0.8335	likely pathogenic
REVEL	0.684	pathogenic-leaning
SaProt	LLR -13.02	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 0.76, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 6,571 bp · p 2.7e-08 · regional, not allelic
Overall
CADD	24.1	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 0.0503% East Asian · 17/33,778 alleles

Filtering AF 0.032% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0263%

Overall 0.0019% 23/1,209,881 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0503%	1,987
Remaining individualsnot grpmax-eligible	0.0105%	9,522
South Asian	0.00176%	56,858

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.Pro565Ser
Coding: c.1693C>T
MANE Select: NM_001110556
dbSNP: rs782580317
Type: single nucleotide variant
Location: chrX:154364956 (GRCh38)
Structure: AlphaFold pLDDT 77.37 · 26 PDB
Residue 565: a β-strand

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

Disease context

heterotopia, periventricular, X-linked dominant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: otopalatodigital syndrome type 2 Melnick-Needles syndrome frontometaphyseal dysplasia

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-pro565ser (accessed [today's date]).

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