Is EXOSC2 p.Ile268Ser (c.803T>G) pathogenic?

EXOSC2 p.Ile268Ser (c.803T>G) is classified Uncertain significance in EXOSC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-04-18). AlphaMissense: ambiguous (0.4693); Very rare (popmax 6.84e-05%); Associated with retinitis pigmentosa-hearing loss-premature aging-short stature-facial dysmorphism syndrome.

How common is EXOSC2 p.Ile268Ser (c.803T>G) in the general population?

EXOSC2 p.Ile268Ser (c.803T>G) is very rare (popmax 6.84e-05%) (gnomAD).

What do computational predictors say about EXOSC2 p.Ile268Ser (c.803T>G)?

AlphaMissense predicts ambiguous (score 0.4693) — an in-silico prediction, not a clinical call.

EXOSC2 p.Ile268Ser

Q: What condition is associated with EXOSC2 p.Ile268Ser (c.803T>G)?

EXOSC2 p.Ile268Ser (c.803T>G) is associated with retinitis pigmentosa-hearing loss-premature aging-short stature-facial dysmorphism syndrome (ClinVar).

c.803T>G · rs1831267496 · VCV1032616

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4693 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Conditions

retinitis pigmentosa-hearing loss-premature aging-short stature-facial dysmorphism syndrome

Computational evidence

Protein change
AlphaMissense	0.4693	ambiguous
REVEL	0.443	indeterminate
SaProt	LLR -11.60	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.5, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 9,979 bp · p 0.3 · regional, not allelic
Overall
CADD	29.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.84e-05%

Overall 6.84e-05% 1/1,461,050 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: EXOSC2
Protein: p.Ile268Ser
Coding: c.803T>G
MANE Select: NM_014285
dbSNP: rs1831267496
Type: single nucleotide variant
Location: chr9:130703695 (GRCh38)
Gene constraint: LOEUF 1.009 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.25 · 8 PDB
Residue 268: a turn

Full EXOSC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

retinitis pigmentosa-hearing loss-premature aging-short stature-facial dysmorphism syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EXOSC2 p.Ile268Met Uncertain significance ★ ⚠ same residue
EXOSC2 p.Lys65Asn Uncertain significance ★★ ⚠ same condition
EXOSC2 p.Met5Val Uncertain significance ★★ ⚠ same condition
EXOSC2 p.Tyr206His Uncertain significance ★★ ⚠ same condition
EXOSC2 p.Gly198Asp Likely pathogenic ★ same condition
EXOSC2 p.Trp204Ter Likely pathogenic ★ same condition
EXOSC2 c.673-1G>T Conflicting classifications of pathogenicity ★ same condition
EXOSC2 c.801+1G>A Conflicting classifications of pathogenicity ★ same condition

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/exosc2-p-ile268ser (accessed [today's date]).

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