Is CFL2 p.His133Arg (c.398A>G) pathogenic?

CFL2 p.His133Arg (c.398A>G) is classified Uncertain significance in CFL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-28). AlphaMissense: likely pathogenic (0.9719); Very rare (popmax 0.0011%, sas); Associated with Inborn genetic diseases.

What condition is associated with CFL2 p.His133Arg (c.398A>G)?

CFL2 p.His133Arg (c.398A>G) is associated with Inborn genetic diseases (ClinVar).

How common is CFL2 p.His133Arg (c.398A>G) in the general population?

CFL2 p.His133Arg (c.398A>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CFL2 p.His133Arg (c.398A>G)?

AlphaMissense predicts likely pathogenic (score 0.9719) — an in-silico prediction, not a clinical call.

CFL2 p.His133Arg

c.398A>G · VCV3266613

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9719 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9719	likely pathogenic
REVEL	0.261	benign-leaning
SaProt	LLR -12.88	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 1,672 bp · p 1.3e-06 · regional, not allelic
Overall
CADD	24.7	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 0.0011% South Asian · 1/90,770 alleles

Overall 0.000138% 2/1,449,816 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	90,770
European (non-Finnish)	8.55e-05%	1,169,284

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.His133Arg
Coding: c.398A>G
MANE Select: NM_138638
Type: single nucleotide variant
Location: chr14:34712968 (GRCh38)
Gene constraint: LOEUF 0.91 · pLI 0.11 (gnomAD)
Structure: AlphaFold pLDDT 88.78 · 11 PDB
Residue 133: the adf-h domain; a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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CFL2 p.Asp42Asn Uncertain significance ★ ⚠ same condition
CFL2 p.Ser147Leu Uncertain significance ★ ⚠ same condition
CFL2 p.Val159Ile Uncertain significance ★ ⚠ same condition
CFL2 c.4-172C>T Uncertain significance ★★ same type
CFL2 c.*1507C>T Uncertain significance ★★ 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/cfl2-p-his133arg (accessed [today's date]).

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