Is FLNB p.Tyr121Phe (c.362A>T) pathogenic?

FLNB p.Tyr121Phe (c.362A>T) is classified Conflicting classifications of pathogenicity in FLNB (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-25). AlphaMissense: ambiguous (0.4889); Rare (popmax 0.873%, afr).

How common is FLNB p.Tyr121Phe (c.362A>T) in the general population?

FLNB p.Tyr121Phe (c.362A>T) is rare (popmax 0.873%, afr) (gnomAD).

What do computational predictors say about FLNB p.Tyr121Phe (c.362A>T)?

AlphaMissense predicts ambiguous (score 0.4889) — an in-silico prediction, not a clinical call.

FLNB p.Tyr121Phe

c.362A>T · rs147846832 · VCV258107

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

ambiguous

0.4889 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.873%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4889	ambiguous
REVEL	0.748	pathogenic-leaning
SaProt	LLR -8.81	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.8, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 89 kb · p 2.4e-13 · regional, not allelic
Overall
CADD	25.3	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 0.873% African / African-American · 654/74,944 alleles

Filtering AF 0.817% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.795%

Overall 0.0439% 708/1,613,884 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.873%	115
Remaining individualsnot grpmax-eligible	0.0496%	2,016
Admixed American	0.0333%	3,000
European (non-Finnish)	0.000254%	393,320

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.Tyr121Phe
Coding: c.362A>T
MANE Select: NM_001457
dbSNP: rs147846832
Type: single nucleotide variant
Location: chr3:58077115 (GRCh38)
Gene constraint: LOEUF 0.504 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.96 · 23 PDB
Residue 121: the calponin-homology (ch) 1 domain; an α-helix; the 'actin-binding' region

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

Similar variants

FLNB c.4390+2T>C Pathogenic/Likely pathogenic ★★ same type
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FLNB p.Arg1948Ter Pathogenic ★★ same type
FLNB p.Arg649Ter Pathogenic ★★ same type
FLNB p.Asp167Gly Likely pathogenic ★★ ⚠ same type
FLNB p.Glu227Lys Pathogenic ★★ same type
FLNB p.Gly168Ser Pathogenic/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-tyr121phe (accessed [today's date]).

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