Is KLHL41 p.Lys89Arg (c.266A>G) pathogenic?

KLHL41 p.Lys89Arg (c.266A>G) is classified Uncertain significance in KLHL41 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-22). AlphaMissense: likely benign (0.0789); Absent from gnomAD v4.1; Associated with nemaline myopathy 9.

What condition is associated with KLHL41 p.Lys89Arg (c.266A>G)?

KLHL41 p.Lys89Arg (c.266A>G) is associated with nemaline myopathy 9 (ClinVar).

How common is KLHL41 p.Lys89Arg (c.266A>G) in the general population?

KLHL41 p.Lys89Arg (c.266A>G) is absent from gnomAD v4.1 (gnomAD).

How is Severe congenital nemaline myopathy inherited?

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

What do computational predictors say about KLHL41 p.Lys89Arg (c.266A>G)?

AlphaMissense predicts likely benign (score 0.0789) — an in-silico prediction, not a clinical call.

KLHL41 p.Lys89Arg

c.266A>G · rs1318936873 · VCV1952456

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0789 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nemaline myopathy 9

Computational evidence

Protein change
AlphaMissense	0.0789	likely benign
REVEL	0.105	moderately benign-leaning
SaProt	LLR -5.43	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.6	GERP -3.1, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 313 bp · p 0.53 · regional, not allelic
Overall
CADD	13.17	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: KLHL41
Protein: p.Lys89Arg
Coding: c.266A>G
MANE Select: NM_006063
dbSNP: rs1318936873
Type: single nucleotide variant
Location: chr2:169510044 (GRCh38)
Gene constraint: LOEUF 0.83 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.48
Residue 89: the btb domain

Full KLHL41 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nemaline myopathy 9 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Severe congenital nemaline myopathy (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

KLHL41 p.Gln343Ter Pathogenic ★★ same condition
KLHL41 p.Ala69Val Uncertain significance ★★ ⚠ same condition
KLHL41 p.Arg155Cys Uncertain significance ★★ ⚠ same condition
KLHL41 p.Arg155His Uncertain significance ★★ ⚠ same condition
KLHL41 p.Arg205Gln Uncertain significance ★★ ⚠ same condition
KLHL41 p.Arg485His Uncertain significance ★★ ⚠ same condition
KLHL41 p.Arg586His Uncertain significance ★★ ⚠ same condition
KLHL41 p.Arg597Ser 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/klhl41-p-lys89arg (accessed [today's date]).

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