Is FLNC p.Asp620His (c.1858G>C) pathogenic?

FLNC p.Asp620His (c.1858G>C) is classified Uncertain significance in FLNC (ClinVar, Single submitter, 1 submitter; last evaluated 2019-03-09). AlphaMissense: likely pathogenic (0.9935); Very rare (popmax 8.47e-05%, nfe); Associated with distal myopathy with posterior leg and anterior hand involvement.

What condition is associated with FLNC p.Asp620His (c.1858G>C)?

FLNC p.Asp620His (c.1858G>C) is associated with distal myopathy with posterior leg and anterior hand involvement, myofibrillar myopathy 5, hypertrophic cardiomyopathy 26 (ClinVar).

How common is FLNC p.Asp620His (c.1858G>C) in the general population?

FLNC p.Asp620His (c.1858G>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about FLNC p.Asp620His (c.1858G>C)?

AlphaMissense predicts likely pathogenic (score 0.9935) — an in-silico prediction, not a clinical call.

FLNC p.Asp620His

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.1858G>C · rs567514134 · VCV576189

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9935 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

distal myopathy with posterior leg and anterior hand involvement

Computational evidence

Protein change
AlphaMissense	0.9935	likely pathogenic · top 5% in FLNC
REVEL	0.905	moderately pathogenic-leaning
SaProt	LLR -15.02	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 11 kb · p 8.4e-13 · regional, not allelic
Overall
CADD	29.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,000 alleles

Overall 0.000124% 2/1,614,082 alleles · very rare exomes 2/1,461,804 · genomes 0/152,278 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,504
European (non-Finnish)grpmax	8.47e-05%	1,179,999

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Asp620His
Coding: c.1858G>C
MANE Select: NM_001458
dbSNP: rs567514134
Type: single nucleotide variant
Location: chr7:128841214 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 620: 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

Also linked: myofibrillar myopathy 5 hypertrophic cardiomyopathy 26

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

Inheritance: Autosomal dominant
Onset: Adolescent, Adult

Similar variants

FLNC p.Asp620Asn Uncertain significance ★★ ⚠ same residue
FLNC p.Asp620del 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
FLNC c.2550+1G>C 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-asp620his (accessed [today's date]).

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