Is CST4 p.Cys94Arg (c.280T>C) pathogenic?

CST4 p.Cys94Arg (c.280T>C) is classified Uncertain significance in CST4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-07). AlphaMissense: likely pathogenic (0.9116); Ultra-rare (popmax 0.0312%, eas).

How common is CST4 p.Cys94Arg (c.280T>C) in the general population?

CST4 p.Cys94Arg (c.280T>C) is ultra-rare (popmax 0.0312%, eas) (gnomAD).

What do computational predictors say about CST4 p.Cys94Arg (c.280T>C)?

AlphaMissense predicts likely pathogenic (score 0.9116) — an in-silico prediction, not a clinical call.

CST4 p.Cys94Arg

c.280T>C · rs758353603 · VCV2463373

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9116 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0312%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9116	likely pathogenic · top 1% in CST4
REVEL	0.371	indeterminate
SaProt	LLR -9.83	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 1.4, phastCons 0.44
Regional constraint	o/e 1.39	unconstrained · MANE · 3,072 bp · p 1.4e-07 · regional, not allelic
Overall
CADD	22.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0312% East Asian · 14/44,888 alleles

Filtering AF 0.0188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0151%

Overall 0.00204% 33/1,614,020 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0312%	3,206
Remaining individualsnot grpmax-eligible	0.0032%	31,243
European (non-Finnish)	0.00144%	69,414

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: CST4
Protein: p.Cys94Arg
Coding: c.280T>C
MANE Select: NM_001899
dbSNP: rs758353603
Type: single nucleotide variant
Location: chr20:23687150 (GRCh38)
Gene constraint: LOEUF 1.874 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.01
Residue 94: a disulfide bond

Full CST4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CST4 p.Ala141Ser Benign ★★ ⚠ same type
CST4 p.Arg3= Benign ★★ same type
CST4 p.Asn40Ser Benign ★★ same type
CST4 p.Leu8Gln Benign ★★ ⚠ same type
CST4 p.Lys96= Benign ★★ same type
CST4 p.Ala16Val Uncertain significance ★ ⚠ same type
CST4 p.Ala18Gly Uncertain significance ★ ⚠ same type
CST4 p.Arg91Cys 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/cst4-p-cys94arg (accessed [today's date]).

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