Is LYST p.Ala554Val (c.1661C>T) pathogenic?

LYST p.Ala554Val (c.1661C>T) is classified Uncertain significance in LYST (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-05). AlphaMissense: likely benign (0.1661); Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

What condition is associated with LYST p.Ala554Val (c.1661C>T)?

LYST p.Ala554Val (c.1661C>T) is associated with Inborn genetic diseases (ClinVar).

How common is LYST p.Ala554Val (c.1661C>T) in the general population?

LYST p.Ala554Val (c.1661C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about LYST p.Ala554Val (c.1661C>T)?

AlphaMissense predicts likely benign (score 0.1661) — an in-silico prediction, not a clinical call.

LYST p.Ala554Val

c.1661C>T · rs575087260 · VCV2556956

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1661 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1661	likely benign
REVEL	0.227	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 42 kb · p 0.00014 · regional, not allelic
Overall
CADD	22.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,060 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.00062% 10/1,613,938 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
South Asian	0.00659%	15,180
Remaining individualsnot grpmax-eligible	0.0016%	62,510
European (non-Finnish)	0.00017%	589,953

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.Ala554Val
Coding: c.1661C>T
MANE Select: NM_000081
dbSNP: rs575087260
Type: single nucleotide variant
Location: chr1:235809157 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LYST p.Ala554= Likely benign ★ same residue
LYST p.Ala1084Thr Uncertain significance ★★ ⚠ same condition
LYST p.Ala1945Thr Uncertain significance ★★ ⚠ same condition
LYST p.Ala2080Pro Uncertain significance ★★ ⚠ same condition
LYST p.Ala2258Pro Uncertain significance ★★ ⚠ same condition
LYST p.Ala243Val Uncertain significance ★★ ⚠ same condition
LYST p.Ala2634Val Uncertain significance ★★ same condition
LYST p.Ala2758Thr 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/lyst-p-ala554val (accessed [today's date]).

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