Is FLNB p.Val839Ala (c.2516T>C) pathogenic?

FLNB p.Val839Ala (c.2516T>C) is classified Conflicting classifications of pathogenicity in FLNB (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-05-09). AlphaMissense: likely pathogenic (0.6938); Very rare (popmax 0.00668%, eas).

How common is FLNB p.Val839Ala (c.2516T>C) in the general population?

FLNB p.Val839Ala (c.2516T>C) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about FLNB p.Val839Ala (c.2516T>C)?

AlphaMissense predicts likely pathogenic (score 0.6938) — an in-silico prediction, not a clinical call.

FLNB p.Val839Ala

c.2516T>C · rs765267560 · VCV2174352

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6938 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6938	likely pathogenic
REVEL	0.874	moderately pathogenic-leaning
SaProt	LLR -9.66	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 35 kb · p 0.0019 · regional, not allelic
Overall
CADD	25.6	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 0.00668% East Asian · 3/44,892 alleles

Filtering AF 0.00223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00198%

Overall 0.00273% 44/1,614,028 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,964
Remaining individualsnot grpmax-eligible	0.0032%	31,238
European (non-Finnish)	0.00305%	32,778
South Asian	0.0022%	45,543
African / African-American	0.00133%	74,930

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: FLNB
Protein: p.Val839Ala
Coding: c.2516T>C
MANE Select: NM_001457
dbSNP: rs765267560
Type: single nucleotide variant
Location: chr3:58111822 (GRCh38)
Gene constraint: LOEUF 0.504 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.96 · 23 PDB

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

Similar variants

FLNB p.Val839Asp Likely pathogenic ★ same residue
FLNB p.Val839Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
FLNB c.4390+2T>C Pathogenic/Likely pathogenic ★★ same type
FLNB c.5110-1G>A Likely pathogenic ★★ same type
FLNB p.Arg1463Ter Pathogenic/Likely pathogenic ★★ same type
FLNB p.Arg1948Ter Pathogenic ★★ same type
FLNB p.Arg649Ter Pathogenic ★★ same type
FLNB p.Asp167Gly Likely pathogenic ★★ ⚠ same type

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/flnb-p-val839ala (accessed [today's date]).

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