Is CYS1 p.Pro91Ser (c.271C>T) pathogenic?

CYS1 p.Pro91Ser (c.271C>T) is classified Uncertain significance in CYS1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-03). AlphaMissense: likely benign (0.1097); Very rare (popmax 0.00477%, eas).

How common is CYS1 p.Pro91Ser (c.271C>T) in the general population?

CYS1 p.Pro91Ser (c.271C>T) is very rare (popmax 0.00477%, eas) (gnomAD).

What do computational predictors say about CYS1 p.Pro91Ser (c.271C>T)?

AlphaMissense predicts likely benign (score 0.1097) — an in-silico prediction, not a clinical call.

CYS1 p.Pro91Ser

c.271C>T · rs1474891826 · VCV2211100

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1097 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00477%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1097	likely benign
REVEL	0.109	moderately benign-leaning
SaProt	LLR -7.20	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 0.98	GERP -0.32, phastCons 0.87
Regional constraint	o/e 1.06	unconstrained · MANE · 21 kb · p 0.36 · regional, not allelic
Overall
CADD	20.5	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 0.00477% East Asian · 1/20,970 alleles

Overall 0.000669% 1/149,552 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: CYS1
Protein: p.Pro91Ser
Coding: c.271C>T
MANE Select: NM_001037160
dbSNP: rs1474891826
Type: single nucleotide variant
Location: chr2:10079953 (GRCh38)
Gene constraint: LOEUF 1.86 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.42
Residue 91: the 'disordered' region

Full CYS1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CYS1 c.318+5G>A Pathogenic ★ same type
CYS1 p.Ala109Ser Uncertain significance ★ ⚠ same type
CYS1 p.Ala109Thr Uncertain significance ★ ⚠ same type
CYS1 p.Ala125Thr Uncertain significance ★ ⚠ same type
CYS1 p.Ala150Val Uncertain significance ★ ⚠ same type
CYS1 p.Ala27Glu Uncertain significance ★ ⚠ same type
CYS1 p.Ala53Val Uncertain significance ★ ⚠ same type
CYS1 p.Ala83Asp 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/cys1-p-pro91ser (accessed [today's date]).

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