Is FLNA p.Val985Ile (c.2953G>A) pathogenic?

FLNA p.Val985Ile (c.2953G>A) is classified Benign/Likely benign in FLNA (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-31). AlphaMissense: likely benign (0.1094); Ultra-rare (popmax 0.0218%, amr); Associated with heterotopia, periventricular, X-linked dominant.

What condition is associated with FLNA p.Val985Ile (c.2953G>A)?

FLNA p.Val985Ile (c.2953G>A) is associated with heterotopia, periventricular, X-linked dominant, otopalatodigital syndrome type 2, Melnick-Needles syndrome (ClinVar).

How common is FLNA p.Val985Ile (c.2953G>A) in the general population?

FLNA p.Val985Ile (c.2953G>A) is ultra-rare (popmax 0.0218%, amr) (gnomAD).

What do computational predictors say about FLNA p.Val985Ile (c.2953G>A)?

AlphaMissense predicts likely benign (score 0.1094) — an in-silico prediction, not a clinical call.

FLNA p.Val985Ile

c.2953G>A · rs781884864 · VCV1039306

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1094 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0218%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

heterotopia, periventricular, X-linked dominant

Computational evidence

Protein change
AlphaMissense	0.1094	likely benign
REVEL	0.552	indeterminate
SaProt	LLR -5.30	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 0.74, phastCons 0.94
Regional constraint	o/e 0.80	unconstrained · MANE · 6,571 bp · p 2.7e-08 · regional, not allelic
Overall
CADD	19.53	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 0.0218% Admixed American · 10/45,777 alleles

Filtering AF 0.0118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.009%

Overall 0.00165% 20/1,209,750 alleles · ultra-rare exomes 18/1,097,969 · genomes 2/111,781 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0218%	4,578
Remaining individualsnot grpmax-eligible	0.0042%	23,795
South Asian	0.00352%	28,422
African / African-American	0.00175%	57,141
European (non-Finnish)	0.000559%	179,015

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.Val985Ile
Coding: c.2953G>A
MANE Select: NM_001110556
dbSNP: rs781884864
Type: single nucleotide variant
Location: chrX:154361562 (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: otopalatodigital syndrome type 2 Melnick-Needles syndrome frontometaphyseal dysplasia

Similar variants

FLNA p.Val985Ala Conflicting classifications of pathogenicity ★ ⚠ 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-val985ile (accessed [today's date]).

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