Is EXOSC8 p.Pro10Ser (c.28C>T) pathogenic?

EXOSC8 p.Pro10Ser (c.28C>T) is classified Uncertain significance in EXOSC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-18). AlphaMissense: likely pathogenic (0.8655); Very rare (popmax 0.00334%, amr).

How common is EXOSC8 p.Pro10Ser (c.28C>T) in the general population?

EXOSC8 p.Pro10Ser (c.28C>T) is very rare (popmax 0.00334%, amr) (gnomAD).

What do computational predictors say about EXOSC8 p.Pro10Ser (c.28C>T)?

AlphaMissense predicts likely pathogenic (score 0.8655) — an in-silico prediction, not a clinical call.

EXOSC8 p.Pro10Ser

c.28C>T · rs764347456 · VCV2808798

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8655 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8655	likely pathogenic
REVEL	0.333	indeterminate
SaProt	LLR -12.57	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.9	GERP 2, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 8,490 bp · p 0.45 · regional, not allelic
Overall
CADD	26.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00334% Admixed American · 2/59,966 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000249% 4/1,608,642 alleles · very rare exomes 4/1,456,420 · genomes 0/152,222 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00334%	29,983
South Asian	0.0011%	90,630
European (non-Finnish)	8.51e-05%	1,175,704

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: EXOSC8
Protein: p.Pro10Ser
Coding: c.28C>T
MANE Select: NM_181503
dbSNP: rs764347456
Type: single nucleotide variant
Location: chr13:37002283 (GRCh38)
Gene constraint: LOEUF 1.944 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.77 · 8 PDB
Residue 10: an α-helix

Full EXOSC8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EXOSC8 p.Arg190Lys Uncertain significance ★★ ⚠ same type
EXOSC8 p.Arg94Gln Uncertain significance ★★ ⚠ same type
EXOSC8 p.Asp143Asn Uncertain significance ★★ ⚠ same type
EXOSC8 p.Asp202Val Uncertain significance ★★ ⚠ same type
EXOSC8 p.Ile170Val Uncertain significance ★★ ⚠ same type
EXOSC8 p.Ile270Phe Uncertain significance ★★ ⚠ same type
EXOSC8 p.Leu50Phe Uncertain significance ★★ same type
EXOSC8 p.Thr71Ala 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/exosc8-p-pro10ser (accessed [today's date]).

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