Is LYST p.Pro1985Arg (c.5954C>G) pathogenic?

LYST p.Pro1985Arg (c.5954C>G) is classified Uncertain significance in LYST (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-08). AlphaMissense: ambiguous (0.3498); Very rare (popmax 0.0033%, sas); Associated with Chediak-Higashi syndrome.

What condition is associated with LYST p.Pro1985Arg (c.5954C>G)?

LYST p.Pro1985Arg (c.5954C>G) is associated with Chediak-Higashi syndrome (ClinVar).

How common is LYST p.Pro1985Arg (c.5954C>G) in the general population?

LYST p.Pro1985Arg (c.5954C>G) is very rare (popmax 0.0033%, sas) (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.Pro1985Arg (c.5954C>G)?

AlphaMissense predicts ambiguous (score 0.3498) — an in-silico prediction, not a clinical call.

LYST p.Pro1985Arg

c.5954C>G · rs746352044 · VCV2003274

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3498 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0033%, sas)

Conditions

Chediak-Higashi syndrome

Computational evidence

Protein change
AlphaMissense	0.3498	ambiguous
REVEL	0.527	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 29 kb · p 2.8e-10 · regional, not allelic
Overall
CADD	26.9	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 0.0033% South Asian · 3/90,842 alleles

Filtering AF 0.000877% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000186% 3/1,612,428 alleles · very rare exomes 3/1,460,592 · genomes 0/151,836 · 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.Pro1985Arg
Coding: c.5954C>G
MANE Select: NM_000081
dbSNP: rs746352044
Type: single nucleotide variant
Location: chr1:235766246 (GRCh38)
Gene constraint: LOEUF 0.505 · pLI <0.01 (gnomAD)
Residue 1985: 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-pro1985arg (accessed [today's date]).

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