Is FLNA p.Arg2003His (c.6008G>A) pathogenic?

FLNA p.Arg2003His (c.6008G>A) is classified Uncertain significance in FLNA (ClinVar, Single submitter, 2 submitters; last evaluated 2025-10-15). AlphaMissense: likely benign (0.152); Ultra-rare (popmax 0.0118%, eas); Associated with heterotopia, periventricular, X-linked dominant.

What condition is associated with FLNA p.Arg2003His (c.6008G>A)?

FLNA p.Arg2003His (c.6008G>A) is associated with heterotopia, periventricular, X-linked dominant, intellectual disability, otopalatodigital syndrome type 2 (ClinVar).

How common is FLNA p.Arg2003His (c.6008G>A) in the general population?

FLNA p.Arg2003His (c.6008G>A) is ultra-rare (popmax 0.0118%, eas) (gnomAD).

What do computational predictors say about FLNA p.Arg2003His (c.6008G>A)?

AlphaMissense predicts likely benign (score 0.152) — an in-silico prediction, not a clinical call.

FLNA p.Arg2003His

c.6008G>A · rs1182812659 · VCV975703

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.152 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0118%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

heterotopia, periventricular, X-linked dominant

Computational evidence

Protein change
AlphaMissense	0.152	likely benign
REVEL	0.176	moderately benign-leaning
SaProt	LLR -6.50	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6	GERP 0.52
Regional constraint	o/e 0.74	unconstrained · MANE · 11 kb · p 3.1e-20 · regional, not allelic
Overall
CADD	23.7	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 0.0118% East Asian · 4/33,796 alleles

Filtering AF 0.00396% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00236%

Overall 0.00132% 16/1,210,766 alleles · ultra-rare exomes 15/1,097,760 · genomes 1/113,006 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0118%	8,449
African / African-American	0.00174%	57,528
European (non-Finnish)	0.00123%	81,401

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.Arg2003His
Coding: c.6008G>A
MANE Select: NM_001110556
dbSNP: rs1182812659
Type: single nucleotide variant
Location: chrX:154353310 (GRCh38)
Structure: AlphaFold pLDDT 77.37 · 26 PDB

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: intellectual disability otopalatodigital syndrome type 2 Melnick-Needles syndrome frontometaphyseal dysplasia

Similar variants

FLNA p.Arg2003Cys 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-arg2003his (accessed [today's date]).

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