Is CLN8 p.Phe143Val (c.427T>G) pathogenic?

CLN8 p.Phe143Val (c.427T>G) is classified Uncertain significance in CLN8 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-06). AlphaMissense: ambiguous (0.3532); Absent from gnomAD v4.1; Associated with neuronal ceroid lipofuscinosis.

What condition is associated with CLN8 p.Phe143Val (c.427T>G)?

CLN8 p.Phe143Val (c.427T>G) is associated with neuronal ceroid lipofuscinosis (ClinVar).

How common is CLN8 p.Phe143Val (c.427T>G) in the general population?

CLN8 p.Phe143Val (c.427T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CLN8 p.Phe143Val (c.427T>G)?

AlphaMissense predicts ambiguous (score 0.3532) — an in-silico prediction, not a clinical call.

CLN8 p.Phe143Val

c.427T>G · rs2130992340 · VCV1429545

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3532 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

neuronal ceroid lipofuscinosis

Computational evidence

Protein change
AlphaMissense	0.3532	ambiguous
REVEL	0.515	indeterminate
SaProt	LLR -6.18	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 9,509 bp · p 0.0075 · regional, not allelic
Overall
CADD	22.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CLN8
Protein: p.Phe143Val
Coding: c.427T>G
MANE Select: NM_018941
dbSNP: rs2130992340
Type: single nucleotide variant
Location: chr8:1771481 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.47 · 3 PDB
Residue 143: the tlc domain

Full CLN8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neuronal ceroid lipofuscinosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CLN8 p.Phe143= Likely benign ★ same residue
CLN8 p.Phe143fs Pathogenic ★ same residue
CLN8 p.Arg204Cys Pathogenic/Likely pathogenic ★★ same condition
CLN8 p.Arg204His Likely pathogenic ★★ same condition
CLN8 p.Arg24Gly Pathogenic ★★ same condition
CLN8 p.Arg70Cys Pathogenic/Likely pathogenic ★★ same condition
CLN8 p.Arg70His Pathogenic/Likely pathogenic ★★ same condition
CLN8 p.Gln255Ter Pathogenic ★★ 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/cln8-p-phe143val (accessed [today's date]).

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