Is FLNA p.Val985Ala (c.2954T>C) pathogenic?

FLNA p.Val985Ala (c.2954T>C) is classified Conflicting classifications of pathogenicity in FLNA (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-02). AlphaMissense: likely benign (0.121); Rare (popmax 0.172%, sas); Associated with heterotopia, periventricular, X-linked dominant.

What condition is associated with FLNA p.Val985Ala (c.2954T>C)?

FLNA p.Val985Ala (c.2954T>C) is associated with heterotopia, periventricular, X-linked dominant, otopalatodigital syndrome type 2, Melnick-Needles syndrome (ClinVar).

How common is FLNA p.Val985Ala (c.2954T>C) in the general population?

FLNA p.Val985Ala (c.2954T>C) is rare (popmax 0.172%, sas) (gnomAD).

What do computational predictors say about FLNA p.Val985Ala (c.2954T>C)?

AlphaMissense predicts likely benign (score 0.121) — an in-silico prediction, not a clinical call.

FLNA p.Val985Ala

c.2954T>C · rs782804253 · VCV1166036

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.121 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.172%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

heterotopia, periventricular, X-linked dominant

Computational evidence

Protein change
AlphaMissense	0.121	likely benign
REVEL	0.797	moderately pathogenic-leaning
SaProt	LLR -5.57	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.2	GERP 1.8, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 6,571 bp · p 2.7e-08 · regional, not allelic
Overall
CADD	18.84	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 0.172% South Asian · 98/56,831 alleles

Filtering AF 0.145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.134%

Overall 0.00827% 100/1,209,705 alleles · rare exomes 97/1,098,036 · genomes 3/111,669 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.172%	580
Remaining individualsnot grpmax-eligible	0.0021%	47,595
European (non-Finnish)	0.000112%	895,087

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.Val985Ala
Coding: c.2954T>C
MANE Select: NM_001110556
dbSNP: rs782804253
Type: single nucleotide variant
Location: chrX:154361561 (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.Val985Ile Benign/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
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-val985ala (accessed [today's date]).

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