Is FLNA p.Pro2256Ser (c.6766C>T) pathogenic?

FLNA p.Pro2256Ser (c.6766C>T) is classified Uncertain significance in FLNA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-11). AlphaMissense: likely benign (0.1635); Very rare (popmax 0.00217%, amr); Associated with frontometaphyseal dysplasia.

What condition is associated with FLNA p.Pro2256Ser (c.6766C>T)?

FLNA p.Pro2256Ser (c.6766C>T) is associated with frontometaphyseal dysplasia, heterotopia, periventricular, X-linked dominant, otopalatodigital syndrome type 2 (ClinVar).

How common is FLNA p.Pro2256Ser (c.6766C>T) in the general population?

FLNA p.Pro2256Ser (c.6766C>T) is very rare (popmax 0.00217%, amr) (gnomAD).

How is Frontometaphyseal dysplasia inherited?

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

What do computational predictors say about FLNA p.Pro2256Ser (c.6766C>T)?

AlphaMissense predicts likely benign (score 0.1635) — an in-silico prediction, not a clinical call.

FLNA p.Pro2256Ser

c.6766C>T · rs1603359077 · VCV1018271

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1635 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00217%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

frontometaphyseal dysplasia

Computational evidence

Protein change
AlphaMissense	0.1635	likely benign
REVEL	0.756	pathogenic-leaning
SaProt	LLR -10.33	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 11 kb · p 3.1e-20 · regional, not allelic
Overall
CADD	24.7	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 0.00217% Admixed American · 1/46,131 alleles

Overall 8.26e-05% 1/1,210,364 alleles · very rare exomes 1/1,096,117 · genomes 0/114,247 · joint denominator

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.Pro2256Ser
Coding: c.6766C>T
MANE Select: NM_001110556
dbSNP: rs1603359077
Type: single nucleotide variant
Location: chrX:154352184 (GRCh38)
Structure: AlphaFold pLDDT 77.37 · 26 PDB

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

Disease context

frontometaphyseal dysplasia — 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

For Frontometaphyseal dysplasia (Orphanet):

Inheritance: Autosomal dominant, X-linked dominant
Onset: Neonatal

Similar variants

FLNA c.1066-1G>A Pathogenic/Likely pathogenic ★★ same condition
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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-pro2256ser (accessed [today's date]).

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