Is FLNA p.Pro2065Ser (c.6193C>T) pathogenic?

FLNA p.Pro2065Ser (c.6193C>T) is classified Uncertain significance in FLNA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-24). AlphaMissense: likely benign (0.1533); Very rare (popmax 0.00592%, eas); Associated with Melnick-Needles syndrome.

What condition is associated with FLNA p.Pro2065Ser (c.6193C>T)?

FLNA p.Pro2065Ser (c.6193C>T) is associated with Melnick-Needles syndrome, heterotopia, periventricular, X-linked dominant, otopalatodigital syndrome type 2 (ClinVar).

How common is FLNA p.Pro2065Ser (c.6193C>T) in the general population?

FLNA p.Pro2065Ser (c.6193C>T) is very rare (popmax 0.00592%, eas) (gnomAD).

What do computational predictors say about FLNA p.Pro2065Ser (c.6193C>T)?

AlphaMissense predicts likely benign (score 0.1533) — an in-silico prediction, not a clinical call.

FLNA p.Pro2065Ser

c.6193C>T · rs1603359334 · VCV807859

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1533 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00592%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Melnick-Needles syndrome

Computational evidence

Protein change
AlphaMissense	0.1533	likely benign
REVEL	0.435	indeterminate
SaProt	LLR -9.76	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.9	GERP 0.7
Regional constraint	o/e 0.74	unconstrained · MANE · 11 kb · p 3.1e-20 · regional, not allelic
Overall
CADD	22.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00592% East Asian · 2/33,779 alleles

Filtering AF 0.000981% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000367%

Overall 0.000826% 10/1,210,201 alleles · very rare exomes 9/1,097,599 · genomes 1/112,602 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00592%	16,889
European (non-Finnish)	0.000894%	111,900

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.Pro2065Ser
Coding: c.6193C>T
MANE Select: NM_001110556
dbSNP: rs1603359334
Type: single nucleotide variant
Location: chrX:154353034 (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 familial thoracic aortic aneurysm and aortic dissection

Similar variants

FLNA p.Pro2065Leu Uncertain significance ★ ⚠ same residue
FLNA p.Pro2065= 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

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-pro2065ser (accessed [today's date]).

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