Is FLNC p.Pro1729Ser (c.5185C>T) pathogenic?

FLNC p.Pro1729Ser (c.5185C>T) is classified Likely pathogenic in FLNC (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-08-15). AlphaMissense: likely pathogenic (0.9644); Absent from gnomAD v4.1; Associated with distal myopathy with posterior leg and anterior hand involvement.

What condition is associated with FLNC p.Pro1729Ser (c.5185C>T)?

FLNC p.Pro1729Ser (c.5185C>T) is associated with distal myopathy with posterior leg and anterior hand involvement (ClinVar).

How common is FLNC p.Pro1729Ser (c.5185C>T) in the general population?

FLNC p.Pro1729Ser (c.5185C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FLNC p.Pro1729Ser (c.5185C>T)?

AlphaMissense predicts likely pathogenic (score 0.9644) — an in-silico prediction, not a clinical call.

FLNC p.Pro1729Ser

Q: How is FLNC-related handgrip and calf weakness-distal myopathy inherited?

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

c.5185C>T · VCV3391421

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9644 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

distal myopathy with posterior leg and anterior hand involvement

Computational evidence

Protein change
AlphaMissense	0.9644	likely pathogenic ✓ concordant with ClinVar
REVEL	0.958	strongly pathogenic-leaning
SaProt	LLR -13.18	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.20	donor loss, 21 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 7.7	phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 2,000 bp · p 0.0021 · regional, not allelic
Overall
CADD	25.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FLNC
Protein: p.Pro1729Ser
Coding: c.5185C>T
MANE Select: NM_001458
Type: single nucleotide variant
Location: chr7:128849564 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1729: a β-strand

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

Disease context

distal myopathy with posterior leg and anterior hand involvement — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For FLNC-related handgrip and calf weakness-distal myopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult

Similar variants

FLNC p.Pro1729= Likely benign ★ same residue
FLNC p.Pro1729His Uncertain significance ★ ⚠ same residue
FLNC p.Pro1729Leu Uncertain significance ★ ⚠ same residue
FLNC c.1047+1G>T Likely pathogenic ★★ same condition
FLNC c.1048-1G>A Likely pathogenic ★★ same condition
FLNC c.1210+1G>A Likely pathogenic ★★ same condition
FLNC c.1549+2T>G Likely pathogenic ★★ same condition
FLNC c.2007+1G>A 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/flnc-p-pro1729ser (accessed [today's date]).

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