Is LYST p.Pro3458= (c.10374G>A) pathogenic?

LYST p.Pro3458= (c.10374G>A) is classified Uncertain significance in LYST (ClinVar, Multiple submitters, 2 submitters; last evaluated 2020-02-06). Very rare (popmax 0.000424%, nfe); Associated with autoinflammatory syndrome.

What condition is associated with LYST p.Pro3458= (c.10374G>A)?

LYST p.Pro3458= (c.10374G>A) is associated with autoinflammatory syndrome, Chediak-Higashi syndrome (ClinVar).

How common is LYST p.Pro3458= (c.10374G>A) in the general population?

LYST p.Pro3458= (c.10374G>A) is very rare (popmax 0.000424%, nfe) (gnomAD).

LYST p.Pro3458=

c.10374G>A · rs1661644862 · VCV1013685

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Conditions

autoinflammatory syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.79	donor loss at this position · masked 0 · deltas
Pangolin	Δ0.67	loss · gain 0.06 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 3.3	GERP 1.6, phastCons 1
Overall
CADD	20.4	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,178,894 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,612,832 alleles · very rare exomes 5/1,460,610 · genomes 0/152,222 · 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: LYST
Protein: p.Pro3458=
Coding: c.10374G>A
MANE Select: NM_000081
dbSNP: rs1661644862
Type: single nucleotide variant
Location: chr1:235702747 (GRCh38)
Gene constraint: LOEUF 0.505 · pLI <0.01 (gnomAD)
Residue 3458: a UniProt-annotated variant site (in chs)

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

Disease context

autoinflammatory syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Chediak-Higashi syndrome

Similar variants

LYST p.Pro3458Gln Uncertain significance ★★ same residue
LYST p.Pro3458Leu Uncertain significance ★★ same residue
LYST p.Pro3458Thr Uncertain significance ★ same residue
LYST c.192+1G>A Pathogenic/Likely pathogenic ★★ same condition
LYST c.4862+2T>A Likely pathogenic ★★ same condition
LYST c.4863-1G>C Likely pathogenic ★★ same condition
LYST c.6882-1G>T Likely pathogenic ★★ same condition
LYST c.8358+2T>C Pathogenic/Likely 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/lyst-p-pro3458 (accessed [today's date]).

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