Is CFL2 p.Leu166Ser (c.497T>C) pathogenic?

CFL2 p.Leu166Ser (c.497T>C) is classified Uncertain significance in CFL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-19). AlphaMissense: likely pathogenic (0.9586); Absent from gnomAD v4.1; Associated with nemaline myopathy 7.

What condition is associated with CFL2 p.Leu166Ser (c.497T>C)?

CFL2 p.Leu166Ser (c.497T>C) is associated with nemaline myopathy 7 (ClinVar).

How common is CFL2 p.Leu166Ser (c.497T>C) in the general population?

CFL2 p.Leu166Ser (c.497T>C) is absent from gnomAD v4.1 (gnomAD).

How is Typical nemaline myopathy inherited?

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

What do computational predictors say about CFL2 p.Leu166Ser (c.497T>C)?

AlphaMissense predicts likely pathogenic (score 0.9586) — an in-silico prediction, not a clinical call.

CFL2 p.Leu166Ser

c.497T>C · rs2502576876 · VCV1713798

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9586 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,506,480)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

nemaline myopathy 7

Computational evidence

Protein change
AlphaMissense	0.9586	likely pathogenic
REVEL	0.407	indeterminate
SaProt	LLR -13.11	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 1,672 bp · p 1.3e-06 · regional, not allelic
Overall
CADD	24.9	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

No allele count reported in gnomAD v4.1 (AN 1,506,480). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CFL2
Protein: p.Leu166Ser
Coding: c.497T>C
MANE Select: NM_138638
dbSNP: rs2502576876
Type: single nucleotide variant
Location: chr14:34712869 (GRCh38)
Gene constraint: LOEUF 0.91 · pLI 0.11 (gnomAD)
Structure: AlphaFold pLDDT 88.78 · 11 PDB

Full CFL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nemaline myopathy 7 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Typical nemaline myopathy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Antenatal, Neonatal
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

CFL2 c.4-172C>T Uncertain significance ★★ same condition
CFL2 c.*1507C>T Uncertain significance ★★ same condition
CFL2 c.*1759A>G Uncertain significance ★★ same condition
CFL2 p.Leu153Val Uncertain significance ★★ ⚠ same condition
CFL2 p.Lys31Asn Uncertain significance ★★ ⚠ same condition
CFL2 p.Met18Ile Uncertain significance ★★ ⚠ same condition
CFL2 p.Thr25Ala Uncertain significance ★★ ⚠ same condition
CFL2 p.Val57Met Uncertain significance ★★ ⚠ 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/cfl2-p-leu166ser (accessed [today's date]).

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