Is FLNC p.Phe92Ile (c.274T>A) pathogenic?

FLNC p.Phe92Ile (c.274T>A) is classified Uncertain significance in FLNC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-01). AlphaMissense: likely pathogenic (0.9958); Very rare (popmax 0.00267%, afr); Associated with FLNC-related disorder.

What condition is associated with FLNC p.Phe92Ile (c.274T>A)?

FLNC p.Phe92Ile (c.274T>A) is associated with FLNC-related disorder (ClinVar).

How common is FLNC p.Phe92Ile (c.274T>A) in the general population?

FLNC p.Phe92Ile (c.274T>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about FLNC p.Phe92Ile (c.274T>A)?

AlphaMissense predicts likely pathogenic (score 0.9958) — an in-silico prediction, not a clinical call.

FLNC p.Phe92Ile

c.274T>A · rs1807861657 · VCV2628961

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9958 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

FLNC-related disorder

Computational evidence

Protein change
AlphaMissense	0.9958	likely pathogenic · top 4% in FLNC
REVEL	0.44	indeterminate
SaProt	LLR -9.48	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 6,570 bp · p 3e-14 · regional, not allelic
Overall
CADD	29.1	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 0.00267% African / African-American · 2/74,932 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,612,948 alleles · very rare exomes 0/1,460,756 · genomes 2/152,192 · joint denominator

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: FLNC
Protein: p.Phe92Ile
Coding: c.274T>A
MANE Select: NM_001458
dbSNP: rs1807861657
Type: single nucleotide variant
Location: chr7:128830911 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 92: the calponin-homology (ch) 1 domain; the 'actin-binding' region

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

Disease context

FLNC-related disorder

Similar variants

FLNC c.4457-1G>C Pathogenic ★★ same condition
FLNC c.7385-1G>A Likely pathogenic ★★ same condition
FLNC c.7780+1G>C Likely pathogenic ★★ same condition
FLNC p.Ala1186Val Pathogenic/Likely pathogenic ★★ same condition
FLNC p.Gln1315Ter Pathogenic/Likely pathogenic ★★ same condition
FLNC p.Ala1105Ser Uncertain significance ★★ same condition
FLNC p.Ala2485Val Uncertain significance ★★ same condition
FLNC p.Arg1657Gly Uncertain significance ★★ 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/flnc-p-phe92ile (accessed [today's date]).

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