Is FLNA p.Arg828Pro (c.2483G>C) pathogenic?

FLNA p.Arg828Pro (c.2483G>C) is classified Conflicting classifications of pathogenicity in FLNA (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-05-28). AlphaMissense: ambiguous (0.5619); Very rare (popmax 0.000782%, nfe); Associated with Melnick-Needles syndrome.

What condition is associated with FLNA p.Arg828Pro (c.2483G>C)?

FLNA p.Arg828Pro (c.2483G>C) is associated with Melnick-Needles syndrome, heterotopia, periventricular, X-linked dominant, otopalatodigital syndrome type 2 (ClinVar).

How common is FLNA p.Arg828Pro (c.2483G>C) in the general population?

FLNA p.Arg828Pro (c.2483G>C) is very rare (popmax 0.000782%, nfe) (gnomAD).

What do computational predictors say about FLNA p.Arg828Pro (c.2483G>C)?

AlphaMissense predicts ambiguous (score 0.5619) — an in-silico prediction, not a clinical call.

FLNA p.Arg828Pro

c.2483G>C · rs1347740802 · VCV533586

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5619 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000782%, nfe)

Conditions

Melnick-Needles syndrome

Computational evidence

Protein change
AlphaMissense	0.5619	ambiguous
REVEL	0.565	indeterminate
SaProt	LLR -4.42	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.6	GERP -0.58
Regional constraint	o/e 0.80	unconstrained · MANE · 6,571 bp · p 2.7e-08 · regional, not allelic
Overall
CADD	21.6	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 0.000782% European (non-Finnish) · 7/895,145 alleles

Filtering AF 0.000325% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000209%

Overall 0.000638% 7/1,097,197 alleles · very rare

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.Arg828Pro
Coding: c.2483G>C
MANE Select: NM_001110556
dbSNP: rs1347740802
Type: single nucleotide variant
Location: chrX:154362500 (GRCh38)
Structure: AlphaFold pLDDT 77.37 · 26 PDB

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

Disease context

Melnick-Needles syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

FLNA p.Arg828His Uncertain significance ★★ ⚠ 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-arg828pro (accessed [today's date]).

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