Is KLHL3 p.Pro559Ser (c.1675C>T) pathogenic?

KLHL3 p.Pro559Ser (c.1675C>T) is classified Uncertain significance in KLHL3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-22). AlphaMissense: ambiguous (0.4144); Very rare (popmax 0.00134%, afr); Associated with Inborn genetic diseases.

What condition is associated with KLHL3 p.Pro559Ser (c.1675C>T)?

KLHL3 p.Pro559Ser (c.1675C>T) is associated with Inborn genetic diseases (ClinVar).

How common is KLHL3 p.Pro559Ser (c.1675C>T) in the general population?

KLHL3 p.Pro559Ser (c.1675C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about KLHL3 p.Pro559Ser (c.1675C>T)?

AlphaMissense predicts ambiguous (score 0.4144) — an in-silico prediction, not a clinical call.

KLHL3 p.Pro559Ser

c.1675C>T · VCV3716326

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4144 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4144	ambiguous
REVEL	0.611	indeterminate
SaProt	LLR -11.13	damaging
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 10	GERP 2.6, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 114 kb · p 1.1e-20 · regional, not allelic
Overall
CADD	26.7	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 0.00134% African / African-American · 1/74,900 alleles

Overall 0.000186% 3/1,614,020 alleles · very rare exomes 2/1,461,892 · genomes 1/152,128 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,243
African / African-Americangrpmax	0.00134%	74,900

Remaining individuals 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: KLHL3
Protein: p.Pro559Ser
Coding: c.1675C>T
MANE Select: NM_017415
Type: single nucleotide variant
Location: chr5:137625813 (GRCh38)
Gene constraint: LOEUF 0.377 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 90.53 · 3 PDB
Residue 559: a UniProt-annotated variant site (in pha2d); a turn

Full KLHL3 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

KLHL3 p.Ala389Thr Uncertain significance ★★ ⚠ same condition
KLHL3 p.Ala77Val Uncertain significance ★★ ⚠ same condition
KLHL3 p.Arg156Cys Uncertain significance ★★ ⚠ same condition
KLHL3 p.Arg156His Uncertain significance ★★ ⚠ same condition
KLHL3 p.Arg430Gln Uncertain significance ★★ ⚠ same condition
KLHL3 p.Arg479Cys Uncertain significance ★★ ⚠ same condition
KLHL3 p.Asn558Ser Uncertain significance ★★ ⚠ same condition
KLHL3 p.Asp166Asn 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/klhl3-p-pro559ser (accessed [today's date]).

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