Is CLN8 p.Phe32Val (c.94T>G) pathogenic?

CLN8 p.Phe32Val (c.94T>G) is classified Uncertain significance in CLN8 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-10-29). AlphaMissense: ambiguous (0.3608); Very rare (popmax 0.00669%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CLN8 p.Phe32Val (c.94T>G)?

CLN8 p.Phe32Val (c.94T>G) is associated with Inborn genetic diseases, neuronal ceroid lipofuscinosis 8, neuronal ceroid lipofuscinosis 8 northern epilepsy variant (ClinVar).

How common is CLN8 p.Phe32Val (c.94T>G) in the general population?

CLN8 p.Phe32Val (c.94T>G) is very rare (popmax 0.00669%, nfe) (gnomAD).

What do computational predictors say about CLN8 p.Phe32Val (c.94T>G)?

AlphaMissense predicts ambiguous (score 0.3608) — an in-silico prediction, not a clinical call.

CLN8 p.Phe32Val

c.94T>G · rs758068226 · VCV195346

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.3608 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3608	ambiguous
REVEL	0.808	moderately pathogenic-leaning
SaProt	LLR -7.92	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 9,509 bp · p 0.0075 · regional, not allelic
Overall
CADD	24.4	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 0.00669% European (non-Finnish) · 79/1,180,020 alleles

Filtering AF 0.00546% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00506%

Overall 0.00539% 87/1,614,070 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0096%	10,418
European (non-Finnish)grpmax	0.00669%	14,937
African / African-American	0.00267%	37,509

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe32Val
Coding: c.94T>G
MANE Select: NM_018941
dbSNP: rs758068226
Type: single nucleotide variant
Location: chr8:1771148 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.47 · 3 PDB

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

Also linked: neuronal ceroid lipofuscinosis 8 neuronal ceroid lipofuscinosis 8 northern epilepsy variant neuronal ceroid lipofuscinosis

Similar variants

CLN8 p.Phe32Leu Uncertain significance ★★ ⚠ 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
CLN8 p.Gln99Ter Pathogenic/Likely 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-phe32val (accessed [today's date]).

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