Is LYST p.Met3526Val (c.10576A>G) pathogenic?

LYST p.Met3526Val (c.10576A>G) is classified Uncertain significance in LYST (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-04). AlphaMissense: likely benign (0.1962); Very rare (popmax 0.004%, afr); Associated with Chediak-Higashi syndrome.

What condition is associated with LYST p.Met3526Val (c.10576A>G)?

LYST p.Met3526Val (c.10576A>G) is associated with Chediak-Higashi syndrome (ClinVar).

How common is LYST p.Met3526Val (c.10576A>G) in the general population?

LYST p.Met3526Val (c.10576A>G) is very rare (popmax 0.004%, afr) (gnomAD).

How is Chédiak-Higashi syndrome inherited?

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

What do computational predictors say about LYST p.Met3526Val (c.10576A>G)?

AlphaMissense predicts likely benign (score 0.1962) — an in-silico prediction, not a clinical call.

LYST p.Met3526Val

c.10576A>G · rs376161116 · VCV3011043

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1962 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Conditions

Chediak-Higashi syndrome

Computational evidence

Protein change
AlphaMissense	0.1962	likely benign
REVEL	0.305	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 71 kb · p 1.5e-17 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/74,932 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,613,994 alleles · very rare

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.Met3526Val
Coding: c.10576A>G
MANE Select: NM_000081
dbSNP: rs376161116
Type: single nucleotide variant
Location: chr1:235693475 (GRCh38)
Gene constraint: LOEUF 0.505 · pLI <0.01 (gnomAD)
Residue 3526: a UniProt-annotated variant site (in chs)

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

Disease context

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

For Chédiak-Higashi syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

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
LYST c.8358+2T>G Likely pathogenic ★★ same condition
LYST c.8802-2A>G Pathogenic/Likely pathogenic ★★ same condition
LYST c.9784+1G>T 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-met3526val (accessed [today's date]).

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