Is CST8 p.Arg5Gln (c.14G>A) pathogenic?

CST8 p.Arg5Gln (c.14G>A) is classified Uncertain significance in CST8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-12). AlphaMissense: likely benign (0.0932); Ultra-rare (popmax 0.0165%, mid).

How common is CST8 p.Arg5Gln (c.14G>A) in the general population?

CST8 p.Arg5Gln (c.14G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CST8 p.Arg5Gln (c.14G>A)?

AlphaMissense predicts likely benign (score 0.0932) — an in-silico prediction, not a clinical call.

CST8 p.Arg5Gln

c.14G>A · VCV3836989

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0932 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0932	likely benign
REVEL	0.019	moderately benign-leaning
SaProt	LLR -6.80	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 -0.46	GERP -3.2
Regional constraint	o/e 1.17	unconstrained · MANE · 4,243 bp · p 0.026 · regional, not allelic
Overall
CADD	8.294	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 0.0165% Middle Eastern · 1/6,078 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00162%

Overall 0.00235% 38/1,613,646 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,078
African / African-American	0.00668%	14,977
Admixed American	0.00333%	29,996
Remaining individualsnot grpmax-eligible	0.0032%	31,228
European (non-Finnish)	0.00237%	42,135

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.Arg5Gln
Coding: c.14G>A
MANE Select: NM_005492
Type: single nucleotide variant
Location: chr20:23491681 (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.Ala91Val Uncertain significance ★ ⚠ same type
CST8 p.Arg115Gly 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
CST8 p.Asp94Tyr Uncertain significance ★ ⚠ same type
CST8 p.Cys105Gly 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-arg5gln (accessed [today's date]).

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