Is CST4 p.Leu101Val (c.301T>G) pathogenic?

CST4 p.Leu101Val (c.301T>G) is classified Uncertain significance in CST4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-01). AlphaMissense: likely benign (0.1459); Ultra-rare (popmax 0.0516%, nfe).

How common is CST4 p.Leu101Val (c.301T>G) in the general population?

CST4 p.Leu101Val (c.301T>G) is ultra-rare (popmax 0.0516%, nfe) (gnomAD).

What do computational predictors say about CST4 p.Leu101Val (c.301T>G)?

AlphaMissense predicts likely benign (score 0.1459) — an in-silico prediction, not a clinical call.

CST4 p.Leu101Val

c.301T>G · rs768223485 · VCV2366454

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1459 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0516%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1459	likely benign
REVEL	0.059	moderately benign-leaning
SaProt	LLR -3.03	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 -1.2	GERP -2.8
Regional constraint	o/e 1.39	unconstrained · MANE · 3,072 bp · p 1.4e-07 · regional, not allelic
Overall
CADD	9.171	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 0.0516% European (non-Finnish) · 609/1,180,028 alleles

Filtering AF 0.0482% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0468%

Overall 0.0414% 669/1,614,136 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0516%	1,938
Remaining individualsnot grpmax-eligible	0.0432%	2,315
South Asian	0.0285%	3,503
African / African-American	0.00533%	18,754
Admixed American	0.00333%	30,007
East Asian	0.00223%	44,886

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.Leu101Val
Coding: c.301T>G
MANE Select: NM_001899
dbSNP: rs768223485
Type: single nucleotide variant
Location: chr20:23687129 (GRCh38)
Gene constraint: LOEUF 1.874 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.01
Residue 101: 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-leu101val (accessed [today's date]).

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