Is KLHL41 p.Arg464= (c.1390A>C) pathogenic?

KLHL41 p.Arg464= (c.1390A>C) is classified Likely benign in KLHL41 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-08). Very rare (popmax 0.00892%, eas); Associated with nemaline myopathy 9.

What condition is associated with KLHL41 p.Arg464= (c.1390A>C)?

KLHL41 p.Arg464= (c.1390A>C) is associated with nemaline myopathy 9 (ClinVar).

How common is KLHL41 p.Arg464= (c.1390A>C) in the general population?

KLHL41 p.Arg464= (c.1390A>C) is very rare (popmax 0.00892%, eas) (gnomAD).

How is Severe congenital nemaline myopathy inherited?

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

KLHL41 p.Arg464=

c.1390A>C · rs778940575 · VCV1153332

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00892%, eas)

Conditions

nemaline myopathy 9

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.9	GERP 0.62, phastCons 1
Overall
CADD	10.75	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00892% East Asian · 4/44,846 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000248% 4/1,611,872 alleles · very rare exomes 4/1,459,520 · genomes 0/152,352 · 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: KLHL41
Protein: p.Arg464=
Coding: c.1390A>C
MANE Select: NM_006063
dbSNP: rs778940575
Type: single nucleotide variant
Location: chr2:169518203 (GRCh38)
Gene constraint: LOEUF 0.83 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.48

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.Arg464Ser Uncertain significance ★ ⚠ same residue
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

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-arg464 (accessed [today's date]).

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