Is CFL2 p.Val57Met (c.169G>A) pathogenic?

CFL2 p.Val57Met (c.169G>A) is classified Uncertain significance in CFL2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-27). AlphaMissense: likely pathogenic (0.6585); Ultra-rare (popmax 0.0135%, nfe); Associated with nemaline myopathy 7.

What condition is associated with CFL2 p.Val57Met (c.169G>A)?

CFL2 p.Val57Met (c.169G>A) is associated with nemaline myopathy 7 (ClinVar).

How common is CFL2 p.Val57Met (c.169G>A) in the general population?

CFL2 p.Val57Met (c.169G>A) is ultra-rare (popmax 0.0135%, nfe) (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.Val57Met (c.169G>A)?

AlphaMissense predicts likely pathogenic (score 0.6585) — an in-silico prediction, not a clinical call.

CFL2 p.Val57Met

c.169G>A · rs200536303 · VCV954128

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.6585 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0135%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

nemaline myopathy 7

Computational evidence

Protein change
AlphaMissense	0.6585	likely pathogenic
REVEL	0.518	indeterminate
SaProt	LLR -9.08	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	Δ0.41	donor loss, 1 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 4.9	phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 1,672 bp · p 1.3e-06 · regional, not allelic
Overall
CADD	29.6	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 0.0135% European (non-Finnish) · 159/1,180,028 alleles

Filtering AF 0.0117% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0111%

Overall 0.0145% 234/1,613,992 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.106%	942
European (non-Finnish)grpmax	0.0135%	7,422
Remaining individualsnot grpmax-eligible	0.008%	12,496
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
South Asian	0.0011%	91,074

Finnish 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: CFL2
Protein: p.Val57Met
Coding: c.169G>A
MANE Select: NM_138638
dbSNP: rs200536303
Type: single nucleotide variant
Location: chr14:34713396 (GRCh38)
Gene constraint: LOEUF 0.91 · pLI 0.11 (gnomAD)
Structure: AlphaFold pLDDT 88.78 · 11 PDB
Residue 57: an α-helix; the adf-h domain; the 'interaction with csrp3' region

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 c.*1682A>T Benign ★★ 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-val57met (accessed [today's date]).

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