Is CST8 p.Val31Glu (c.92T>A) pathogenic?

CST8 p.Val31Glu (c.92T>A) is classified Uncertain significance in CST8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-29). AlphaMissense: likely benign (0.1255); Very rare (popmax 0.000763%, nfe).

How common is CST8 p.Val31Glu (c.92T>A) in the general population?

CST8 p.Val31Glu (c.92T>A) is very rare (popmax 0.000763%, nfe) (gnomAD).

What do computational predictors say about CST8 p.Val31Glu (c.92T>A)?

AlphaMissense predicts likely benign (score 0.1255) — an in-silico prediction, not a clinical call.

CST8 p.Val31Glu

c.92T>A · rs751450947 · VCV3078422

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1255 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1255	likely benign
REVEL	0.039	moderately benign-leaning
SaProt	LLR -6.30	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 -0.095	GERP -1.1
Regional constraint	o/e 1.17	unconstrained · MANE · 4,243 bp · p 0.026 · regional, not allelic
Overall
CADD	14.04	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 0.000763% European (non-Finnish) · 9/1,179,928 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000684% 10/1,461,826 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,506
European (non-Finnish)grpmax	0.000763%	131,103

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CST8
Protein: p.Val31Glu
Coding: c.92T>A
MANE Select: NM_005492
dbSNP: rs751450947
Type: single nucleotide variant
Location: chr20:23491759 (GRCh38)
Gene constraint: LOEUF 1.952 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.12

Full CST8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CST8 p.Val31Leu Uncertain significance ★ ⚠ same residue
CST8 p.Ala91Val Uncertain significance ★ ⚠ same type
CST8 p.Arg115Gly Uncertain significance ★ ⚠ same type
CST8 p.Arg5Gln Uncertain significance ★ ⚠ same type
CST8 p.Asn102Asp Uncertain significance ★ ⚠ same type
CST8 p.Asn27Lys Uncertain significance ★ ⚠ same type
CST8 p.Asn39Asp Uncertain significance ★ ⚠ same type
CST8 p.Asn44Lys 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/cst8-p-val31glu (accessed [today's date]).

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