Is LYST p.Pro462Ser (c.1384C>T) pathogenic?

LYST p.Pro462Ser (c.1384C>T) is classified Benign/Likely benign in LYST (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-31). AlphaMissense: likely benign (0.0834); Rare (popmax 0.853%, afr); Associated with autoinflammatory syndrome.

What condition is associated with LYST p.Pro462Ser (c.1384C>T)?

LYST p.Pro462Ser (c.1384C>T) is associated with autoinflammatory syndrome, Chediak-Higashi syndrome (ClinVar).

How common is LYST p.Pro462Ser (c.1384C>T) in the general population?

LYST p.Pro462Ser (c.1384C>T) is rare (popmax 0.853%, afr) (gnomAD).

What do computational predictors say about LYST p.Pro462Ser (c.1384C>T)?

AlphaMissense predicts likely benign (score 0.0834) — an in-silico prediction, not a clinical call.

LYST p.Pro462Ser

c.1384C>T · rs77848653 · VCV454481

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0834 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.853%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

autoinflammatory syndrome

Computational evidence

Protein change
AlphaMissense	0.0834	likely benign
REVEL	0.038	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.5	GERP 2.3, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 42 kb · p 0.00014 · regional, not allelic
Overall
CADD	18.34	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 0.853% African / African-American · 640/74,994 alleles

Filtering AF 0.799% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.777%

Overall 0.0447% 721/1,613,820 alleles · rare exomes 338/1,461,684 · genomes 383/152,136 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.853%	117
Admixed American	0.0634%	1,578
Remaining individualsnot grpmax-eligible	0.0592%	1,689
South Asian	0.0022%	45,534
European (non-Finnish)	0.000339%	294,989

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.Pro462Ser
Coding: c.1384C>T
MANE Select: NM_000081
dbSNP: rs77848653
Type: single nucleotide variant
Location: chr1:235809434 (GRCh38)
Gene constraint: LOEUF 0.505 · pLI <0.01 (gnomAD)

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.Pro462Leu Uncertain significance ★ ⚠ same residue
LYST p.Pro462= Likely benign ★ 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
LYST c.8358+2T>G 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-pro462ser (accessed [today's date]).

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