Is CLN8 p.Val38Phe (c.112G>T) pathogenic?

CLN8 p.Val38Phe (c.112G>T) is classified Uncertain significance in CLN8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-10-02). AlphaMissense: ambiguous (0.3649); Ultra-rare (popmax 0.022%, sas); Associated with neuronal ceroid lipofuscinosis.

What condition is associated with CLN8 p.Val38Phe (c.112G>T)?

CLN8 p.Val38Phe (c.112G>T) is associated with neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis 8 (ClinVar).

How common is CLN8 p.Val38Phe (c.112G>T) in the general population?

CLN8 p.Val38Phe (c.112G>T) is ultra-rare (popmax 0.022%, sas) (gnomAD).

What do computational predictors say about CLN8 p.Val38Phe (c.112G>T)?

AlphaMissense predicts ambiguous (score 0.3649) — an in-silico prediction, not a clinical call.

CLN8 p.Val38Phe

c.112G>T · rs370199508 · VCV970037

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3649 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.022%, sas)

Conditions

neuronal ceroid lipofuscinosis

Computational evidence

Protein change
AlphaMissense	0.3649	ambiguous
REVEL	0.572	indeterminate
SaProt	LLR -9.24	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.3	GERP 2, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 9,509 bp · p 0.0075 · regional, not allelic
Overall
CADD	24.8	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 0.022% South Asian · 20/91,076 alleles

Filtering AF 0.0145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.0015% 22/1,461,888 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.022%	4,554
Remaining individualsnot grpmax-eligible	0.0016%	62,506
European (non-Finnish)	8.47e-05%	1,180,011

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.Val38Phe
Coding: c.112G>T
MANE Select: NM_018941
dbSNP: rs370199508
Type: single nucleotide variant
Location: chr8:1771166 (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

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

Also linked: neuronal ceroid lipofuscinosis 8

Similar variants

CLN8 p.Val38Ile Uncertain significance ★★ ⚠ same residue
CLN8 p.Val38= Likely benign ★ same residue
CLN8 p.Val38fs 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

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-val38phe (accessed [today's date]).

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