Is CST4 p.Leu48Val (c.142C>G) pathogenic?

CST4 p.Leu48Val (c.142C>G) is classified Uncertain significance in CST4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-15). AlphaMissense: likely benign (0.185); Very rare (popmax 0.00223%, eas).

How common is CST4 p.Leu48Val (c.142C>G) in the general population?

CST4 p.Leu48Val (c.142C>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CST4 p.Leu48Val (c.142C>G)?

AlphaMissense predicts likely benign (score 0.185) — an in-silico prediction, not a clinical call.

CST4 p.Leu48Val

c.142C>G · VCV3269959

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.185 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.185	likely benign
REVEL	0.094	moderately benign-leaning
SaProt	LLR -8.00	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 -0.84	GERP -3.1
Regional constraint	o/e 1.39	unconstrained · MANE · 3,072 bp · p 1.4e-07 · regional, not allelic
Overall
CADD	6.935	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 0.00223% East Asian · 1/44,852 alleles

Overall 6.84e-05% 1/1,461,886 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: CST4
Protein: p.Leu48Val
Coding: c.142C>G
MANE Select: NM_001899
Type: single nucleotide variant
Location: chr20:23688828 (GRCh38)
Gene constraint: LOEUF 1.874 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.01

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-leu48val (accessed [today's date]).

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