Is FLNC p.Pro1997Leu (c.5990C>T) pathogenic?

FLNC p.Pro1997Leu (c.5990C>T) is classified Uncertain significance in FLNC (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-27). AlphaMissense: likely pathogenic (0.7429); Very rare (popmax 8.48e-05%, nfe); Associated with myofibrillar myopathy 5.

What condition is associated with FLNC p.Pro1997Leu (c.5990C>T)?

FLNC p.Pro1997Leu (c.5990C>T) is associated with myofibrillar myopathy 5, distal myopathy with posterior leg and anterior hand involvement, hypertrophic cardiomyopathy 26 (ClinVar).

How common is FLNC p.Pro1997Leu (c.5990C>T) in the general population?

FLNC p.Pro1997Leu (c.5990C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is Muscle filaminopathy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about FLNC p.Pro1997Leu (c.5990C>T)?

AlphaMissense predicts likely pathogenic (score 0.7429) — an in-silico prediction, not a clinical call.

FLNC p.Pro1997Leu

c.5990C>T · rs2536659542 · VCV2057996

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7429 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

myofibrillar myopathy 5

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.7429	likely pathogenic
REVEL	0.224	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense calls this damaging; REVEL does not; SaProt makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 4	phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 5,636 bp · p 8.4e-23 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,724 alleles

Overall 6.2e-05% 1/1,613,156 alleles · very rare exomes 1/1,460,808 · genomes 0/152,348 · 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.Pro1997Leu
Coding: c.5990C>T
MANE Select: NM_001458
dbSNP: rs2536659542
Type: single nucleotide variant
Location: chr7:128852738 (GRCh38)

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

Disease context

myofibrillar myopathy 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: distal myopathy with posterior leg and anterior hand involvement hypertrophic cardiomyopathy 26

For Muscle filaminopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

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-pro1997leu (accessed [today's date]).

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