Is CLN8 p.Phe234Ile (c.700T>A) pathogenic?

CLN8 p.Phe234Ile (c.700T>A) is classified Uncertain significance in CLN8 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-02-03). AlphaMissense: likely pathogenic (0.8189); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CLN8 p.Phe234Ile (c.700T>A)?

CLN8 p.Phe234Ile (c.700T>A) is associated with Inborn genetic diseases (ClinVar).

How common is CLN8 p.Phe234Ile (c.700T>A) in the general population?

CLN8 p.Phe234Ile (c.700T>A) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CLN8 p.Phe234Ile (c.700T>A)?

AlphaMissense predicts likely pathogenic (score 0.8189) — an in-silico prediction, not a clinical call.

CLN8 p.Phe234Ile

c.700T>A · rs1563114301 · VCV590039

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8189 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8189	likely pathogenic
REVEL	0.505	indeterminate
SaProt	LLR -4.36	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 9,509 bp · p 0.0075 · regional, not allelic
Overall
CADD	21.6	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,036 alleles

Overall 6.19e-05% 1/1,614,236 alleles · very rare exomes 1/1,461,894 · genomes 0/152,342 · joint denominator

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: CLN8
Protein: p.Phe234Ile
Coding: c.700T>A
MANE Select: NM_018941
dbSNP: rs1563114301
Type: single nucleotide variant
Location: chr8:1780406 (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 234: the tlc domain

Full CLN8 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

CLN8 p.Phe234= Likely benign ★ same residue
CLN8 p.Tyr158Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
CLN8 p.Ala19Val Uncertain significance ★★ ⚠ same condition
CLN8 p.Ala239Val Uncertain significance ★★ ⚠ same condition
CLN8 p.Ala80Thr Uncertain significance ★★ ⚠ same condition
CLN8 p.Arg54Cys Uncertain significance ★★ ⚠ same condition
CLN8 p.Arg54His Uncertain significance ★★ ⚠ same condition
CLN8 p.Asn118Thr 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/cln8-p-phe234ile (accessed [today's date]).

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