Is CYSLTR1 p.Pro321Ala (c.961C>G) pathogenic?

CYSLTR1 p.Pro321Ala (c.961C>G) is classified Uncertain significance in CYSLTR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-06). AlphaMissense: likely benign (0.0794); Very rare (popmax 0.00887%, eas).

How common is CYSLTR1 p.Pro321Ala (c.961C>G) in the general population?

CYSLTR1 p.Pro321Ala (c.961C>G) is very rare (popmax 0.00887%, eas) (gnomAD).

What do computational predictors say about CYSLTR1 p.Pro321Ala (c.961C>G)?

AlphaMissense predicts likely benign (score 0.0794) — an in-silico prediction, not a clinical call.

CYSLTR1 p.Pro321Ala

c.961C>G · VCV4009086

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0794 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00887%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0794	likely benign
REVEL	0.032	moderately benign-leaning
SaProt	LLR -6.17	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.88	GERP 0.62, phastCons 0.5
Regional constraint	o/e 1.20	unconstrained · MANE · 1,010 bp · p 0.002 · regional, not allelic
Overall
CADD	0.044	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00887% East Asian · 3/33,822 alleles

Filtering AF 0.00235% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00125%

Overall 0.000274% 3/1,096,209 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: CYSLTR1
Protein: p.Pro321Ala
Coding: c.961C>G
MANE Select: NM_006639
Type: single nucleotide variant
Location: chrX:78272786 (GRCh38)
Structure: AlphaFold pLDDT 85.79 · 2 PDB

Full CYSLTR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CYSLTR1 p.Arg121Trp Conflicting classifications of pathogenicity ★ ⚠ same type
CYSLTR1 p.Arg22His Uncertain significance ★ ⚠ same type
CYSLTR1 p.Arg253His Uncertain significance ★ ⚠ same type
CYSLTR1 p.Arg79His Uncertain significance ★ ⚠ same type
CYSLTR1 p.Arg79Leu Uncertain significance ★ ⚠ same type
CYSLTR1 p.Arg97His Uncertain significance ★ ⚠ same type
CYSLTR1 p.Asn287Ser Uncertain significance ★ ⚠ same type
CYSLTR1 p.Asn6Asp Uncertain significance ★ ⚠ same type

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/cysltr1-p-pro321ala (accessed [today's date]).

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