Is KLHL40 p.Ser288= (c.864C>T) pathogenic?

KLHL40 p.Ser288= (c.864C>T) is classified Conflicting classifications of pathogenicity in KLHL40 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-24). Ultra-rare (popmax 0.029%, eas); Associated with nemaline myopathy 8.

What condition is associated with KLHL40 p.Ser288= (c.864C>T)?

KLHL40 p.Ser288= (c.864C>T) is associated with nemaline myopathy 8 (ClinVar).

How common is KLHL40 p.Ser288= (c.864C>T) in the general population?

KLHL40 p.Ser288= (c.864C>T) is ultra-rare (popmax 0.029%, eas) (gnomAD).

How is Severe congenital nemaline myopathy inherited?

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

KLHL40 p.Ser288=

c.864C>T · rs374925596 · VCV651780

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.029%, eas)

Conditions

nemaline myopathy 8

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 -8.4	GERP -4.5
Overall
CADD	0.285	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.029% East Asian · 13/44,882 alleles

Filtering AF 0.0171% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00204% 33/1,614,056 alleles · ultra-rare exomes 28/1,461,776 · genomes 5/152,280 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.029%	3,452
South Asian	0.0165%	6,072
Remaining individualsnot grpmax-eligible	0.008%	12,500

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: KLHL40
Protein: p.Ser288=
Coding: c.864C>T
MANE Select: NM_152393
dbSNP: rs374925596
Type: single nucleotide variant
Location: chr3:42686482 (GRCh38)
Gene constraint: LOEUF 1.128 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.70 · 1 PDB
Residue 288: a UniProt-annotated variant site (in nem8); the 'disordered' region

Full KLHL40 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

nemaline myopathy 8 — 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

KLHL40 c.1608-1G>A Pathogenic ★★ same condition
KLHL40 p.Arg500Cys Pathogenic/Likely pathogenic ★★ same condition
KLHL40 p.Arg59Pro Likely pathogenic ★★ same condition
KLHL40 p.Gln497Ter Pathogenic/Likely pathogenic ★★ same condition
KLHL40 p.Glu235Ter Pathogenic/Likely pathogenic ★★ same condition
KLHL40 p.Glu528Lys Pathogenic/Likely pathogenic ★★ same condition
KLHL40 p.Thr506Pro Pathogenic ★★ same condition
KLHL40 p.Trp201Ter Pathogenic ★★ 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/klhl40-p-ser288 (accessed [today's date]).

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