Is FLNC p.Pro875Ser (c.2623C>T) pathogenic?

FLNC p.Pro875Ser (c.2623C>T) is classified Uncertain significance in FLNC (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-30). AlphaMissense: likely pathogenic (0.5953); Very rare (popmax 8.48e-05%, nfe).

How common is FLNC p.Pro875Ser (c.2623C>T) in the general population?

FLNC p.Pro875Ser (c.2623C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about FLNC p.Pro875Ser (c.2623C>T)?

AlphaMissense predicts likely pathogenic (score 0.5953) — an in-silico prediction, not a clinical call.

FLNC p.Pro875Ser

c.2623C>T · VCV4975691

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5953 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5953	likely pathogenic
REVEL	0.777	moderately pathogenic-leaning
SaProt	LLR -8.96	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 11 kb · p 8.4e-13 · regional, not allelic
Overall
CADD	25.4	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 8.48e-05% European (non-Finnish) · 1/1,179,568 alleles

Overall 6.2e-05% 1/1,612,970 alleles · very rare exomes 0/1,460,752 · genomes 1/152,218 · 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.Pro875Ser
Coding: c.2623C>T
MANE Select: NM_001458
Type: single nucleotide variant
Location: chr7:128843301 (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

Similar variants

FLNC p.Pro875Arg Uncertain significance ★ ⚠ same residue
FLNC c.1047+1G>T Likely pathogenic ★★ same type
FLNC c.1048-1G>A Likely pathogenic ★★ same type
FLNC c.1210+1G>A Likely pathogenic ★★ same type
FLNC c.1549+2T>G Likely pathogenic ★★ same type
FLNC c.2007+1G>A Likely pathogenic ★★ same type
FLNC c.2550+1G>C Likely pathogenic ★★ same type
FLNC c.2550+2T>C Pathogenic/Likely pathogenic ★★ same type

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-pro875ser (accessed [today's date]).

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