Is FLNA p.Pro2126Ser (c.6376C>T) pathogenic?

FLNA p.Pro2126Ser (c.6376C>T) is classified Conflicting classifications of pathogenicity in FLNA (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-07-31). AlphaMissense: ambiguous (0.5267); Ultra-rare (popmax 0.0131%, nfe); Associated with Melnick-Needles syndrome.

How common is FLNA p.Pro2126Ser (c.6376C>T) in the general population?

FLNA p.Pro2126Ser (c.6376C>T) is ultra-rare (popmax 0.0131%, nfe) (gnomAD).

What do computational predictors say about FLNA p.Pro2126Ser (c.6376C>T)?

AlphaMissense predicts ambiguous (score 0.5267) — an in-silico prediction, not a clinical call.

FLNA p.Pro2126Ser

Q: What condition is associated with FLNA p.Pro2126Ser (c.6376C>T)?

FLNA p.Pro2126Ser (c.6376C>T) is associated with Melnick-Needles syndrome, intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked, heterotopia, periventricular, X-linked dominant (ClinVar).

c.6376C>T · rs782400832 · VCV533577

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.5267 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0131%, nfe)

Conditions

Melnick-Needles syndrome

Computational evidence

Protein change
AlphaMissense	0.5267	ambiguous
REVEL	0.626	indeterminate
SaProt	LLR -11.12	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 11 kb · p 3.1e-20 · regional, not allelic
Overall
CADD	26.1	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 0.0131% European (non-Finnish) · 117/895,337 alleles

Filtering AF 0.0111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0104%

Overall 0.00991% 120/1,210,891 alleles · ultra-rare exomes 118/1,097,848 · genomes 2/113,043 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0131%	7,652
Remaining individualsnot grpmax-eligible	0.0042%	23,809
African / African-American	0.00174%	57,571

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.Pro2126Ser
Coding: c.6376C>T
MANE Select: NM_001110556
dbSNP: rs782400832
Type: single nucleotide variant
Location: chrX:154352775 (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: intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked heterotopia, periventricular, X-linked dominant terminal osseous dysplasia-pigmentary defects syndrome FG syndrome 2 otopalatodigital syndrome type 2 otopalatodigital syndrome type 1 cardiac valvular dysplasia, X-linked frontometaphyseal dysplasia frontometaphyseal dysplasia 1

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-pro2126ser (accessed [today's date]).

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