Is EXOSC5 p.Val155Phe (c.463G>T) pathogenic?

EXOSC5 p.Val155Phe (c.463G>T) is classified Uncertain significance in EXOSC5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-03). AlphaMissense: likely pathogenic (0.6433); Ultra-rare (popmax 0.0229%, nfe); Associated with Inborn genetic diseases.

What condition is associated with EXOSC5 p.Val155Phe (c.463G>T)?

EXOSC5 p.Val155Phe (c.463G>T) is associated with Inborn genetic diseases (ClinVar).

How common is EXOSC5 p.Val155Phe (c.463G>T) in the general population?

EXOSC5 p.Val155Phe (c.463G>T) is ultra-rare (popmax 0.0229%, nfe) (gnomAD).

What do computational predictors say about EXOSC5 p.Val155Phe (c.463G>T)?

AlphaMissense predicts likely pathogenic (score 0.6433) — an in-silico prediction, not a clinical call.

EXOSC5 p.Val155Phe

c.463G>T · rs202054918 · VCV2507585

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6433 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0229%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6433	likely pathogenic
REVEL	0.49	indeterminate
SaProt	LLR -12.41	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.004	GERP -3, phastCons 0.001
Regional constraint	o/e 0.96	unconstrained · MANE · 11 kb · p 0.52 · regional, not allelic
Overall
CADD	21.8	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 0.0229% European (non-Finnish) · 270/1,180,026 alleles

Filtering AF 0.0206% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.0171% 276/1,614,056 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0229%	4,370
Remaining individualsnot grpmax-eligible	0.0064%	15,623
African / African-American	0.00267%	37,462

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: EXOSC5
Protein: p.Val155Phe
Coding: c.463G>T
MANE Select: NM_020158
dbSNP: rs202054918
Type: single nucleotide variant
Location: chr19:41389827 (GRCh38)
Gene constraint: LOEUF 1.136 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.59 · 8 PDB
Residue 155: a β-strand

Full EXOSC5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EXOSC5 p.Ala137Thr Uncertain significance ★★ ⚠ same condition
EXOSC5 p.Glu174Gly Uncertain significance ★★ same condition
EXOSC5 p.Thr17Ile Uncertain significance ★★ ⚠ same condition
EXOSC5 p.Ala104Val Uncertain significance ★ ⚠ same condition
EXOSC5 p.Ala150Thr Uncertain significance ★ ⚠ same condition
EXOSC5 p.Ala216Thr Uncertain significance ★ same condition
EXOSC5 p.Ala56Val Uncertain significance ★ ⚠ same condition
EXOSC5 p.Arg149Gln Uncertain significance ★ ⚠ 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/exosc5-p-val155phe (accessed [today's date]).

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