Is FLNC p.Pro1234Ser (c.3700C>T) pathogenic?

FLNC p.Pro1234Ser (c.3700C>T) is classified Uncertain significance in FLNC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-20). AlphaMissense: likely benign (0.0936); Very rare (popmax 0.000254%, nfe); Associated with hypertrophic cardiomyopathy 26.

What condition is associated with FLNC p.Pro1234Ser (c.3700C>T)?

FLNC p.Pro1234Ser (c.3700C>T) is associated with hypertrophic cardiomyopathy 26, myofibrillar myopathy 5, distal myopathy with posterior leg and anterior hand involvement (ClinVar).

How common is FLNC p.Pro1234Ser (c.3700C>T) in the general population?

FLNC p.Pro1234Ser (c.3700C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about FLNC p.Pro1234Ser (c.3700C>T)?

AlphaMissense predicts likely benign (score 0.0936) — an in-silico prediction, not a clinical call.

FLNC p.Pro1234Ser

c.3700C>T · rs2536638457 · VCV2933562

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0936 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hypertrophic cardiomyopathy 26

Computational evidence

Protein change
AlphaMissense	0.0936	likely benign
REVEL	0.361	indeterminate
SaProt	LLR -8.72	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 11 kb · p 8.4e-13 · regional, not allelic
Overall
CADD	19.35	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.000254% European (non-Finnish) · 3/1,180,040 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,928 alleles · very rare exomes 3/1,461,598 · genomes 0/152,330 · 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.Pro1234Ser
Coding: c.3700C>T
MANE Select: NM_001458
dbSNP: rs2536638457
Type: single nucleotide variant
Location: chr7:128845165 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)

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

Disease context

hypertrophic cardiomyopathy 26 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: myofibrillar myopathy 5 distal myopathy with posterior leg and anterior hand involvement

Similar variants

FLNC p.Pro1234= Likely benign ★★ 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
FLNC c.2550+2T>C Pathogenic/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-pro1234ser (accessed [today's date]).

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